Methods and compositions comprising a 5ht receptor agonist for the treatment of psychological, cognitive, behavorial, and/or mood disorders

ABSTRACT

Provided herein are methods and compositions for the treatment of psychological, cognitive, behavioral, and/or mood disorders, the composition comprising a 5HT agonist (e.g. psilocybin). In certain embodiments, such compositions are administered in amounts or levels high enough to provide a therapeutic effect, but insufficient to provide an adverse effect.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Patent ApplicationNo. 62/798,998 filed on Jan. 30, 2019 and U.S. Provisional PatentApplication No. 62/799,010 filed on Jan. 30, 2019, each incorporatedherein by reference in its entirety.

BACKGROUND

The serotonin (5HT) receptors are a group of G protein-coupled receptors(GPCRs) and ligand-gated ion channels found in the central andperipheral nervous systems. Activation of 5HT receptors cansubstantially influence brain function.

Many people worldwide are afflicted with psychological or mooddisorders, such as depression, anxiety, compulsion, and post-traumaticstress disorders, among others. Many of these conditions are believed toinvolve a person's serotonin system, including interactions between (A)the neurotransmitter serotonin and (B) several different subtypes ofserotonin neurotransmitter receptors found in the human body.

A variety of compositions are known to modulate activity at theserotonin receptors. A number of pharmaceuticals (antidepressants,serotonin reuptake inhibitors, selective serotonin reuptake inhibitors,etc.) have become commercially available. Many leading commercialpharmaceutical products for treating mood disorders (such as depression,obsessive-compulsive disorder, and/or anxiety disorders) targetserotonin pathways.

However, despite their popularity and commercial success, thesepharmaceutical products are characterized by their long onset times,severe side-effects, and poor efficacy. In many cases, these drugs areharmful to the user. For example, many people taking prescription drugstargeting serotonin report feeling suicidal thoughts, sexualdysfunction, fatigue, elevated blood pressure, blurred vision, abnormalheart rate, nausea, and weight gain.

Psilocybin (also known as 4-phosphoryloxy-N,N-dimethyltryptamine or[3-(2-trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) isconsidered to be the most abundant psychoactive compound within a “magicmushroom.” Psilocybin has also been tested for its potential indeveloping prescription drugs to treat drug dependence, anxiety and mooddisorders. However, therapeutic applications of psilocybin to date aretied with its adverse side effects, including hallucinations, panicattacks, psychosis, nausea, vomiting, muscle weakness, and lack ofcoordination. Accordingly, there is a need to develop pharmaceuticalcompositions of psilocybin for treating disorders associated with 5HTreceptors without the adverse side effects.

SUMMARY

Provided herein in certain embodiments are methods and compositions forthe treatment of psychological, cognitive, behavioral, and/or mooddisorders. In some embodiments, a disorder described herein is treatedby administration of a therapeutically effective amount of a agentdescribed herein, such as a 5HT agonist (such as an active 5HT agonistitself (e.g., psilocin), or a salt, solvate, metabolite, derivative, orprodrug thereof (e.g., psilocybin)). In certain embodiments, such agentsare administered at (or are present in a composition provided herein in)an amount or level high enough to provide a therapeutic effect, e.g.,but high enough to avoid an adverse effect (e.g., hallucinogenic orother adverse effect, such as panic attacks, psychosis, nausea,vomiting, muscle weakness, or lack of coordination) (e.g., a low dose,therapeutically effective amount). In certain instances, such low dosetherapeutics (and/or compositions or methods provided herein) provideimproved motivation, attention, accuracy, speed of response,perseveration, and/or cognitive engagement. In some embodiments such lowdose therapeutics (and/or compositions or methods provided herein) areused in the treatment of behavioral and/or cognitive disorders, such aswhere motivation, attention, accuracy, speed of response, perseverance,and/or cognitive engagement play a role. In certain embodiments,compositions provided herein are useful in or used in the treatmentdepression, anxiety, apathy and/or low motivation, attention disorders,disorders of executive function and/or cognitive engagement, obsessivecompulsive disorder, and/or neurocognitive disorders.

Also provided herein in some embodiments is a method of managing aneurological condition or one or more symptoms thereof in a subject inneed thereof, comprising administering to the subject a pharmaceuticalcomposition comprising:

a) a therapeutically effective amount of one or more 5HT receptoragonist (e.g., psilocin) or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof (e.g., psilocybin); and

b) a pharmaceutically acceptable excipient.

In some embodiments, the therapeutically effective amount of the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to the subject inneed thereof in an amount insufficient to provide an adverse sideeffect, such as hallucinogenic experience.

Also provided herein is a method of treating the symptoms of aneurological condition in a subject suffering from or susceptible to theneurological condition, comprising administering to the subject apharmaceutical composition comprising:

a) a therapeutically effective amount of one or more 5HT receptoragonist (e.g., psilocin) or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof (e.g., psilocybin); and

b) a pharmaceutically acceptable excipient.

In specific embodiments, the therapeutically effective amount of the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to the subject inneed thereof in an amount insufficient to provide an adverse sideeffect, such as hallucinogenic experience.

In some embodiments, the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ispresent in an amount of from about 0.1 mg to about 50 mg (e.g. about 0.1mg to about 10 mg, about 0.2 mg to about 5 mg, about 10 mg to about 50mg, or the like).

In some embodiments, the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ispresent in an amount of from about 0.1 mg to about 2 mg.

In some embodiments, the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ispresent in an amount of from about 1 mg to about 15 mg.

In some embodiments, the pharmaceutical composition is a low-dosepharmaceutical composition.

In some embodiments, the pharmaceutical composition comprises acontrolled release component.

In some embodiments, the pharmaceutical composition comprises acontrolled release component and an immediate release component.

In some embodiments, the therapeutically effective amount of 5HTreceptor agonist (e.g., psilocin) or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof (e.g., psilocybin)is provided to a subject in need thereof in an amount and/or formulationinsufficient to provide a maximum plasma concentration (C_(max)) of(e.g. active form of the) 5HT receptor agonist (e.g., psilocin) or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof of 6 ng/mL or more.

In some embodiments, the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug (e.g., psilocybin) thereof isprovided to a subject in need thereof in an amount and/or formulation toprovide a maximum plasma concentration (C_(max)) of (e.g. active form ofthe) 5HT receptor agonist (e.g., psilocin) or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ofabout 0.1 ng/mL or more and less than 6 ng/mL (e.g. at least 0.5 ng/mLand less than 6 ng/mL, about 1 ng/mL to about 5.5 ng/mL, about 2 ng/mLto about 5 ng/mL, or the like).

In some embodiments, the therapeutically effective amount of 5HTreceptor agonist (e.g., psilocin) or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof is provided to asubject in need thereof in an amount and/or formulation to provide aplasma concentration of (e.g. active form of the) 5HT receptor agonist(e.g., psilocin) or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of at least 0.1 ng/mL (e.g.at least 0.2 ng/mL, at least 0.3 ng/mL, at least 0.5 ng/mL, or the like)after at least 6 hours (e.g. at least 12 hours, at least 24 hours, atleast 36 hours, at least 48 hours, at least 72 hours, at least 96 hours,at least 120 hours, at least 144 hours, or the like).

In some embodiments, the 5HT receptor agonist is a 5HT2 receptoragonist. In some embodiments, the 5HT receptor agonist is psilocybin ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Also disclosed herein is a pharmaceutical composition comprising:

a) a therapeutically effective amount of one or more 5HT receptoragonist (e.g., psilocin) or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof (e.g., psilocybin),

b) a pharmaceutically acceptable excipient, and

c) (e.g., optionally) one or more agents selected from the groupconsisting of surfactants, preservatives, flavoring agents, sweeteningagents, and antifoaming agents.

Also disclosed herein is a pharmaceutical composition comprising:

a) a therapeutically effective amount of one or more 5HT receptoragonist (e.g., psilocin) or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof (e.g., psilocybin),

b) a pharmaceutically acceptable excipient, and

c) (e.g., optionally) one or more agents selected from the groupconsisting of surfactants, preservatives, flavoring agents, sweeteningagents, and antifoaming agents;

In some embodiments, a pharmaceutical composition provided herein is alow-dose pharmaceutical composition. In some embodiments, followingadministration to an individual in need thereof, a pharmaceuticalcomposition provided herein provides a maximum plasma concentration(C_(max)) of the 5HT receptor agonist (e.g., psilocin) (or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug (e.g., psilocybin) thereof) of less than 6 ng/mL (e.g., theactive form of the 5HT receptor agonist, regardless of the formadministered) in the individual in need thereof. In some embodiments,the 5HT receptor agonist is psilocin or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof. In someembodiments, the 5HT receptor agonist is psilocybin or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Also disclosed herein is a pharmaceutical composition comprising an oraldosage form, the oral dosage form comprising an immediate-release toplayer and a controlled release core. In some embodiments, theimmediate-release layer comprising (i) one or more 5HT receptor agonistor a pharmaceutically acceptable salt, solvate, metabolite, derivative,or prodrug thereof and (ii) one or more second agent. In someembodiments, the one or more second agent being a stimulant, anantihistamine, an antiemetic, an antidepressant, an anti-inflammatory, agrowth factor, a lithium compound, resveratrol, phosphatidylcholine,curcumin, magnesium, melatonin, pregnenolone, ginseng, or lysergic aciddiethylamide. In certain embodiments, the controlled release corecomprises (a) one or more 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof;(b) at least one pharmaceutically acceptable excipient; and (c)optionally one or more agents selected from the group consisting ofsurfactants, preservatives, flavoring agents, sweetening agents, andantifoaming agents. In some embodiments, the pharmaceutical compositionis a low-dose pharmaceutical composition. In certain embodiments,following administration to an individual in need thereof, thepharmaceutical composition provides a maximum plasma concentration(Cmax) of the 5HT receptor agonist (or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof) of less than6 ng/mL (e.g., the active form of the 5HT receptor agonist, regardlessof the form administered) in the individual in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the disclosure are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, andthe accompanying drawings of which:

FIG. 1 shows the effects of psilocybin on locomotor activity andbehavior signs in treated rats. A) Graph shows distance traveled(measured in cm) against doses of psilocybin ranging from 0.03-10 mg/kg.B) Graph shows effects of psilocybin dosing on 5-HT_(2A)-relatedbehaviors. The total number (N) of wet dog shakes (WDS) and back musclecontractions (BMC) is plotted against dose (mg/kg). Hatched shadingindicates psilocybin doses which evoked statistically identical WDS andBMC behaviors as Vehicle.

FIG. 2 shows the effects of psilocybin on progressive ratio (PR) test intreated rats. A) Graph shows number of lever presses prior to treatmentwith vehicle or psilocybin, by high and low responder rat groups, toestablish pre-test PR baseline. B) Graph shows number of lever pressesby high and low responder rat subgroups across psilocybin doses of 0.05mg/kg, 0.1 mg/kg and 0.2 mg/kg. High responders are defined as ratscompleting the highest tertile of lever presses in the baseline test;low responders are rats completing the bottom tertile of lever pressesin the baseline test. Asterisk (*) indicates statistical significancebetween high and low responders.

FIG. 3 shows the effects of psilocybin on cognition in rats using the5-choice serial reaction time task (5-CSRTT) with 5 second inter-trialinterval. A) Graph shows pro-cognitive effects (measured as % Hitregarding nose-poke to stimulation location to collect a food reward) ofpsilocybin 0.05 mg/kg dose versus vehicle and 0.1 mg/kg dose across allrats. Asterisk (*) indicates statistical difference vs. vehicle. B)Graph shows pro-cognitive effects (measured as % Correct regardingaccuracy in nose-poke) of psilocybin 0.05 mg/kg dose versus vehicle and0.1 mg/kg dose across all rats. C) Graph shows pro-cognitive effect oftwo different doses of psilocybin on low performer subgroup (% Hit).Asterisk (*) indicates statistical difference vs. vehicle D) Graph showseffect of two different doses of psilocybin on low performer subgroup (%Correct). High performers are defined as rats completing the highesttertile of Hits or Correct nose-pokes in the baseline test; lowperformers are rats completing the bottom tertile of Hits or Correctnose-pokes in the baseline test.

FIG. 4 shows the effects of psilocybin on cognition in rats using5-choice serial reaction time task (5-CSRTT) and evaluating prematureresponses (PREM) and perseverative responses (PSV). A) Graphs showincrease in PREM and PSV responses under a 5 second inter-trial interval(ITI) which establishes a baseline (Base) and a 10 second ITI across 24animals across two doses of psilocybin (0.05 mg/kg and 0.1 mg/kg).Standard deviation is indicated by error bars; asterisks (*) indicatesignificance vs. vehicle (P=0.05) using T-test. B) Graphs show effectsof psilocybin on PREM and PSV in low performer and high performersubgroups. Standard error of the mean is indicated by error bars;asterisks (*) indicate significance vs. vehicle (P<0.01) using T-test.High performers are defined as rats with the highest tertile ofpremature responses in the baseline test; low performers are rats withthe bottom tertile of premature responses in the baseline test.

FIG. 5 shows the blood plasma levels over time of psilocin in rats dosedwith psilocybin at several dose levels: 0.05 mg/kg (C_(max) psilocin˜6±2 ng/ml (after 30 mins)) or 0.1 mg/kg (C_(max) psilocin ˜12±3 ng/ml(after 30 mins)), 1 mg/kg (C_(max) psilocin ˜83±5 ng/ml (after 30mins)), 10 mg/kg (C_(max) psilocin ˜1106±164 ng/ml (after 30 mins)).

FIG. 6 shows the effects of psilocybin on cognition in rats. A) Graphshows the lowest performing tertile (N=8) low attentive and potentiallyrepresentative of a low attentive endophenotype of depression. B) Graphshows % hit score for low attentive rats. D) Graph shows a slowerresponse speed for low attentive rats. Similar to the PR test, theeffect of 0.05 and 0.1 mg/kg psilocybin on accuracy (% correct and %hit) in the 5CSRTT was observed to be strongly evident in the lowattentive subgroup compared with vehicle C) graph and E) graph. Asterisk(*) indicates statistical significance vs. vehicle. Psilocybin 0.05mg/kg also increased response speed in the low attentive cohort comparedwith vehicle D) graph.

DETAILED DESCRIPTION 5HT (or Serotonin) Receptors

The 5HT (or serotonin) receptors are a group of G protein-coupledreceptors (GPCR) and ligand-gated ion channels. 5HT is short for5-hydroxy-tryptamine, the chemical name for serotonin:

The serotonin receptors are activated by serotonin, their naturalligand, and mediate both excitatory and inhibitory neurotransmission.They modulate the release of many neurotransmitters, includingglutamate, GABA, dopamine, epinephrine/norepinephrine and acetylcholine,as well as many hormones, including oxytocin, prolactin, vasopressin,cortisol, corticotropin and substance P. The serotonin receptorsinfluence various biological and neurological processes such asaggression, anxiety, appetite, cognition, learning, memory, mood,nausea, sleep, and thermoregulation.

The 5HT receptors are divided into 7 families of G protein-coupledreceptors. 5HT₁, 5HT₂, 5HT₃ are the major families; the others, 5HT₄,5HT₅, 5HT₆ and 5HT₇, for the most part, work in a similar fashion toeither 5HT₁ or 5HT₂ receptors. The 5HT receptors work with a G proteinto modify an ion channel or membrane enzyme.

In certain embodiments, the 5HT agonist of a formulation, composition,method, or the like described herein is a 5HT₁ agonist. 5HT₁ receptorshave strong binding affinity for serotonin. Typically, when serotoninbinds to a 5HT₁ receptor, a G-protein is activated, opening an ionchannel and allowing potassium ions to exit the neuron. This generallycauses the neuron to become more negatively charged, making it moredifficult to trigger an action potential, i.e. serotonin binding to 5HT₁receptors is an inhibitory effect.

In some preferred embodiments, the 5HT agonist of a formulation,composition, method, or the like described herein is a 5HT₂ agonist. Incertain embodiments, the 5HT₂ agonist has a relatively high affinity for5HT₂ receptors (e.g. relative to 5HT1 receptors and/or other 5HTreceptors, such as 5HT₃, 5HT₄, 5HT₅, 5HT₆, 5HT₇, or all or somecombination thereof, such as 2×, 3×, 5×, 10×, 20×, 50×, or the likegreater affinity). 5HT2 receptors have weaker affinity for serotonin. Assuch, serotonin prefers to bind 5HT₁ receptors, typically only binding5HT₂ receptors once the 5HT₁ receptors are at least partially (orwholly) saturated. Serotonin binding of 5HT₂ receptors typicallyactivates a G-protein closing a potassium channel resulting in potassiumion build up. This generally causes depolarization, making it easier toreach the neuron's excitation threshold. Thus, when serotonin binds to5HT₂ receptors, it typically has an excitatory effect.

Family Type Mechanism Potential 5HT₁ Protein coupled Decreasing cellularInhibitory levels of cAMP 5HT₂ Protein coupled Increasing cellularExcitatory levels of IP₃ and DAG 5HT₃ Ligand-gated Depolarizing plasmaExcitatory Na⁺ and K⁺ membrane cation channel 5HT₄ Protein coupledIncreasing cellular Excitatory levels of cAMP 5HT₅ Protein coupledDecreasing cellular Inhibitory levels of cAMP 5HT₆ Protein coupledIncreasing cellular Excitatory levels of cAMP 5HT₇ Protein coupledIncreasing cellular Excitatory levels of cAMP

The seven serotonin receptor families include fourteen receptorsubtypes, distributed throughout the body as shown in the table below:

Central Peripheral 5HT Blood nervous nervous Smooth Receptor vesselssystem system GI Tract Platelets Muscle 1A ✓ ✓ 1B ✓ ✓ 1D ✓ ✓ 1E ✓ ✓ 1F ✓2A ✓ ✓ ✓ ✓ ✓ ✓ 2B ✓ ✓ ✓ ✓ ✓ ✓ 2C ✓ ✓ ✓ ✓ ✓ ✓ 3 ✓ ✓ ✓ 4 ✓ ✓ ✓ 5A ✓ 5B 6 ✓7 ✓ ✓ ✓

5HT₂ Receptors

In general, 5HT₂ receptors are characterized by having lower affinityfor serotonin (and other indole alkylamines), and are linked to theG_(q)/phospholipase C pathway of signal transduction. In variousinstances, such receptors mediate a variety of physiological andbehavioral function via three distinct subtypes: 5HT_(2A), 5HT_(2B) and5HT_(2C).

Receptor Physiological/behavioral function 5HT_(2A) Addiction, Anxiety,Appetite, Cognition, Imagination, Learning, Memory, Mood, Perception,Sexual Behavior, Sleep, Thermoregulation, Vasoconstriction 5HT_(2B)Anxiety, Appetite, Cardiovascular Function, GI Motility, Sleep,Vasoconstriction 5HT_(2C) Addiction, Anxiety, Appetite, GI Motility,Locomotion, Mood, Penile Erection, Sexual Behavior, Sleep,Thermoregulation, Vasoconstriction

Receptor Uses of drugs that act on this receptor 5HT_(2A)Antipsychotics, Psychedelics, Noradrenergic and Specific SerotonergicAntidepressants (NaSSAs), Sleeping aids 5HT_(2B) Migraines 5HT_(2C)Antidepressant, Orexigenic, Anorectic, Antipsychotic

Receptor Drugs acting on receptor Agonists 5HT_(2A) Bufotenin,Ergonovine, Lisuride, LSD, Mescaline, Myristicin, Psilocin, Psilocybin,DMT, DOM, PNU-22394, TFMPP, 25I-NBOMe, 2C-B, 5-MeO- DMT, BZP AntagonistsAtypical antipsychotics, Clozapine, Olanzapine, Quetiapine, Risperidone,Ziprasidone, Aripiprazole, Asenapine, Amitriptyline, Clomipramine,Cyproheptadine, Eplivanserin, Etoperidone, Haloperidol, Hydroxyzine,Iloperidone, Ketanserin, Methysergide, Mianserin, Mirtazapine,Nefazodone, Pimavanserin, Pizotifen, Ritanserin, Trazodone, YohimbineAgonists 5HT_(2B) Fenfluramine, MDMA, Norfenfluramine, Methylphenidate6-APB, BW-723C86, PNU-22394, Ro60-0175 Antagonists Agomelatine,Asenapine, Ketanserin, Methysergide, Ritanserin, Tegaserod, Yohimbine,BZP, RS-127,445 Agonists Aripiprazole, Ergonovine, Lorcaserin, TrazodonePNU-22394, Ro60-0175, TFMPP, YM-348, A-372,159, AL-38022A Antagonists5HT_(2C) Agomelatine, Amitriptyline, Asenapine, Clomipramine, Clozapine,Cyproheptadine, Dimebolin, Eltoprazine, Etoperidone, Fluoxetine,Haloperidol, Iloperidone, Ketanserin, Lisuride, Methysergide, Mianserin,Mirtazapine, Nefazodone, Olanzapine, Paroxetine, Quetiapine,Risperidone, Ritanserin, Tramadol, Trazodone, Ziprasidone, SB-242084

5HT_(2A) is an important excitatory serotonin receptor subtype. In someinstances, physiological processes mediated by the receptor include, byway of non-limiting example:

-   -   central nervous system—neuronal excitation, behavioral effects,        learning, anxiety, and pro-nociception    -   smooth muscle contraction (in bronchi and gastrointestinal        tract)    -   vasoconstriction/vasodilation    -   platelet aggregation    -   role in memory and learning    -   anti-inflammatory activity    -   hormone (oxytocin, prolactin, ACTH, corticosterone, renin)        regulation    -   mood regulation (depressed patients have more 5HT_(2A) receptors        than otherwise normal individuals implying 5HT_(2A) is involved        in the pathogenesis of depression)

In some instances, agonism of 5HT_(2A) agonism facilitates treatment ormanagement of disorders involving cognitive function and socialinteraction, or the symptoms thereof, as evidenced by the extensivelocalization of the 5HT_(2A) receptor in brain areas that mediatecognitive functions and social interaction. In some instances, disordersin which the 5HT_(2A) receptor are involved include, but are not limitedto schizophrenia, depression/suicide, anxiety, obsessive compulsivedisorders (OCD), bipolar disorders, attention deficit hyperactivitydisorder (ADHD), eating disorders such as anorexia nervosa, autism andautism spectrum disorders, Asperger's, neuropsychiatric diseases anddisorders, sexual disorders such as erectile dysfunction,neurodegenerative diseases, inflammatory diseases, autoimmune diseases,metabolic diseases such as obesity and diabetes, central nervous systemdisorders, peripheral nervous system disorders, Alzheimer's disease,snoring, sleep apnea (obstructive sleep apnea, central sleep apnea),insomnia, sleep deprivation, restless legs syndrome, parasomnia,nightmares, night terrors, sleepwalking, hypersomnia (daytimesleepiness), narcolepsy and pain.

Any suitable 5HT (e.g. 5HT₂, such as 5HT_(2A)) agonist is utilized inany composition, formulation, method, therapy, or the like describedherein. In some preferred embodiments, the 5HT agonist of a formulation,composition, method, or the like described herein is a 5HT_(2A) agonist.In certain embodiments, the 5HT_(2A) agonist has a relatively highaffinity for 5HT_(2A) receptors (e.g, relative to 5HT1, 5HT₃, 5HT₄,5HT₅, 5HT₆, 5HT₇, 5HT_(2B), 5HT_(2C), or all or some combinationthereof, such as 2×, 3×, 5×, 110×, 20×, 50×, or the like greateraffinity). In some instances, 5HT_(2A) agonists increase dopamine levelsin the prefrontal cortex. In certain embodiments, the 5HT_(2A) agonistprovided herein is one of the following classes of 5HT_(2A) agonists:the ergolines, tryptamines and phenethylamines. In specific embodiments,a. 5HT (e.g. 5HT_(2A)) receptor agonist utilized herein is an ergoline:

In some instances, ergonovine and ergotamine, synthetic derivativesinclude the oxytocic methergine, the anti-migraine drugsdihydroergotamine and methysergide, hydergine (a mixture ofdihydroergotoxine mesylates, INN: ergoline mesylates), andbromocriptine. In certain instances, synthetic ergolines includepergolide and lisuride.

In certain instances, the ergoline is an ergoline derivative, such as alysergic acid amide or a peptide alkaloid, such as described below. Insome instances, the ergoline is a clavine (examples includefestuclavine, fumigaclavine A, fumigaclavine B and fumigaclavine C) andother derivatives that do not fall into these categories, such ascabergoline, pergolide, lisuride.

Lysergic Acid Amides

Exemplary lysergic acid amides include Ergine (LSA, D-lysergic acidamide), Ergonovine (ergobasine), Methergine (ME-277), Methysergide(UML-491), LSD (D-lysergic acid diethylamide), LSH (D-lysergic acidα-hydroxyethylamide). The table below summarizes their structuralformula and relationships,

Name R¹ R² R³ Ergine H H H Ergonovine H CH(CH₃)CH₂OH H Methergine HCH(CH₂CH₃)CH₂OH H Methysergide CH₃ CH(CH₂CH₃)CH₂OH H LSD H CH₂CH₃ CH₂CH₃LSH H CH(OH)CH₃ H

Peptide Alkaloids

Exemplary peptide alkaloids include peptide ergot alkaloids(ergopeptines or ergopeptides), which are ergoline derivativescontaining a tripeptide structure (attached at the same position as theamide group of the lysergic acid derivatives) comprising proline and twoother α-amino acids. Examples include:

Ergotoxines (valine at R²)—Ergocristine, Ergocornine, α-Ergocryptine,β-ErgocryptineErgotamines (alanine at R²)—Ergotamine, Ergovaline, α-Ergosine,β-Ergosine

R³ Name R¹ R² R³ acid Amino Ergocristine CH(CH₃)₂ benzyl PhenylalanineErgocornine CH(CH₃)₂ CH(CH₃)₂ Valine α-Ergocryptine CH(CH₃)₂ CH₂CH(CH₃)₂Leucine β-Ergocryptine CH(CH₃)₂ (S)- Isoleucine CH(CH₃)CH₂CH₃ ErgotamineCH₃ benzyl Phenylalanine Ergovaline CH₃ CH(CH₃)₂ Valine α-Ergosine CH₃CH₂CH(CH₃)₂ Leucine β-Ergosine CH₃ (S)- Isoleucine CH(CH₃)CH₂CH₃Bromocriptine Br CH(CH₃)₂ CH₂CH(CH₃)₂ Leucine

Tryptamines

Tryptamine (2-(1H-Indol-3-yl)ethanamine) comprises an indole ringattached to an aminoethylene group. Substituted tryptamines aresubstituted with any suitable group, such as being modified on theindole ring (R¹, R²), the ethylene chain (R³) and/or on the amino group(R⁴, R⁵) as illustrated below, and are collectively referred to hereinas tryptamines. Examples of tryptamines include serotonin, melatonin,psilocybin and N,N-dimethyltryptamine. Additionally, the tryptaminestructure may comprise part of a more complex compound, for example:LSD, ibogaine, mitragynine, yohimbine, etc.

Examples of naturally occurring substituted tryptamines include, by wayof non limiting example:

Short/Common Name Full Name R¹ R² R³ R⁴ R⁵ Tryptamine3-(2-aminoethyl)indole H H H H H 2-(1H-indo1-3-yl)ethanamine Bufotenin5-hydroxy-N,N- OH H H CH₃ CH₃ dimethyltryptamine Nω-5-hydroxy-N-methyltryptamine OH H H CH₃ H Methylserotonin (norbufotenin)Serotonin 5-hydroxytryptamine OH H H H H NMT N-methyltryptamine H H H HCH₃ 5-MeO-NMT 5-methoxy-N-methyltryptamine OCH₃ H CH₃ H H DMTN,N-dimethyltryptamine H H H CH₃ CH₃ 5-Bromo-DMT5-bromo-N,N-dimethyltryptamine Br H H CH₃ CH₃ 5-MeO-DMT 5-methoxy-N,N-OCH₃ H H CH₃ CH₃ dimethyltryptamine Melatonin5-methoxy-N-acetyltryptamine OCH₃ H H C(O)CH₃ H N-Acetylserotonin5-hydroxy-N-acetyltryptamine OH H H C(O)CH₃ H Norbaeocystin4-phosphoryloxy-tryptamine H OPO₃H₂ H H H Baeocystin4-phosphoryloxy-N-methyl- H OPO₃H₂ H CH₃ H tryptamine Psilocybin4-phosphoryloxy-N,N- H PO₄ H CH₃ CH₃ dimethyltryptamine Psilocin4-hydroxy-N,N- H OH H CH₃ CH₃ dimethyltryptamine Tryptophanα-carboxyltryptamine H H COOH H H

Examples of synthetic substituted tryptamines include, by way ofnon-limiting example:

Short Name Name R¹ R² R³ R⁴ R⁵ αET α-ethyltryptamine H H CH₂CH₃ H H αMTα-methyltryptamine H H CH₃ H H DALT N,N-diallyltryptamine H H HH₂C═CH—CH₂ H₂C═CH—CH₂ DET N,N-diethyltryptamine H H H CH₂CH₃ CH₂CH₃ DiPTN,N-diisopropyltryptamine H H H CH(CH₃)₂ CH(CH₃)₂ DPTN,N-dipropyltryptamine H H H CH₂CH₂CH₃ CH₂CH₂CH₃ 5-MeO-αMT 5-methoxy-αOCH₃ H CH₃ H H methyltryptamine 5-MeO- 5-methoxy-N,N- OCH₃ H HH₂C═CH—CH₂ H₂C═CH—CH₂ DALT diallyltryptamine 5-MeO-5-methoxy-N-Methyl-N- OCH₃ H H H₂C═CH—CH₂ CH₃ MALT allyltryptamine H4-HO-DET 4-hydroxy-N,N- H OH H CH₂CH₃ CH₂CH₃ diethyltryptamine 4-AcO-DMT4-acetoxy-N,N- H OCOCH₃ H CH₃ CH₃ dimethyltryptamine 4-HO-MET4-hydroxy-N-methyl-N- H OH H CH₃ CH₂CH₃ ethyltryptamine 4-HO-DIPT4-hydroxy-N,N- H OH H CH(CH₃)₂ CH(CH₃)₂ diisopropyltryptamine 5-MeO-DIPT5-methoxy-N,N- OCH₃ H H CH(CH₃)₂ CH(CH₃)₂ diisopropyltryptamine 5-MeO-5-methoxy-N,N- OCH₃ H H CH₃ CH(CH₃)₂ MiPT methylisopropyltryptamine4-HO-MiPT 4-hydroxy-N-isopropyl-N- H OH H CH(CH₃)₂ CH₃ methyltryptamineSumatriptan 5-(methylamino CH₂SO₂NHCH₃ H H CH₃ CH₃sulfonylmethylene)-N,N- dimethyltryptamine Zolmitriptan 5-(4-(S)-1,3-oxazolidin-2- CHNHC(O)OCH₂ H H CH₃ CH₃ one)-N,N-dimethyl-tryptamine

Phenethylamines

Phenethylamine comprises a phenyl ring attached to an aminoethylenegroup; substituted phenethylamines are optionally substituted in anysuitable manner, such as they are optionally modified by substitution onthe phenyl ring (R¹, R², R³, R⁴ and/or R⁵), the ethylene chain (R⁶and/or R⁷) and/or on the amino group (R⁸, and/or R⁹), such asillustrated below.

Examples of phenethylamines include, but are not limited to thosepresented in the table below:

Substitution Short Name Full Name Amino Ethylene Phenyl Biologicalactivity Amphetamine α-methylphenethylamine ✓ Stimulant β-Methylβ-methylphenethylamine ✓ Stimulant phenethylamine Mephedrone4-methylmethcathinone ✓ ✓ ✓ Stimulant Ethcathinone N-ethylcathinone ✓ ✓Stimulant Ephedrine /N-methyl-β- ✓ ✓ Stimulant; Pseudoephedrinehydroxyamphetamine decongestant Methamphetamine N-methylamphetamine ✓ ✓Stimulant; neurotoxin Phentermine α-methylamphetamine ✓ Stimulant,anorectic Ortetamine 2-methylamphetamine ✓ ✓ Stimulant, anorecticAmfepramone N-diethyl-β- ✓ ✓ Anorectic (diethylpropion) ketoamphetaminePhenylephrine β,3-dihydroxy-N- ✓ ✓ ✓ Decongestant methylphenethylamineMethylphenidate N,α-butylene-β-methoxy ✓ ✓ Stimulant; NDRIcarbonylphenethylamine Dopamine 3,4- ✓ Catecholaminedihydroxyphenethylamine neurotransmitter 6- 2,4,5-trihydroxy ✓Neurotoxic agent Hydroxydopamine phenethylamine Epinephrineβ-3,4-trihydroxy-N- ✓ ✓ ✓ Catecholamine (Adrenaline)methylphenethylamine neurotransmitter Norepinephrine β-3,4-trihydroxy ✓✓ Catecholamine (Noradrenaline) phenethylamine neurotransmitterpara-Octopamine β-4-dihydroxy ✓ ✓ Trace aminergic α- phenethylamineadrenoceptor agonist Salbutamol β-4-dihydroxy-3- ✓ ✓ ✓ Short-action β2-hydroxymethyl-N-tert- adrenergic agonist butylphenethylamine N-MethylN-methylphenethylamine ✓ Amphetamine isomer phenethylamine Cathined-β-hydroxyamphetamine ✓ Releasing agent Cathinone β-ketoamphetamine ✓Releasing agent Methcathinone N-methylcathinone ✓ ✓ Releasing agentBupropion 3-chloro-N-tert-butyl-β- ✓ ✓ ✓ NDRI ketoamphetamineNorfenfluramine 3-trifluoromethyl- ✓ ✓ SSRA amphetamine Fenfluramine3-trifluoromethyl-N- ✓ ✓ ✓ SSRA ethylamphetamine Mescaline3,4,5-trimethoxy ✓ Psychedelic phenethylamine Proscaline2-(3,5-dimethoxy-4- ✓ Psychedelic propoxyphenyl)ethanamine Metaescaline2-(3-ethoxy-4,5- ✓ Psychedelic dimethoxyphenyl)ethanamine Allylescaline4-Allyloxy-3,5- ✓ Psychedelic dimethyloxy phenylethylamineMethallylescaline 4-Methallyloxy-3,5- ✓ Psychedelicdimethoxyphenethylamine Asymbescaline 3,4-Diethoxy-5- ✓ Psychedelicmethoxyphenethylamine

In certain embodiments, a composition or formulation described hereincomprises an antidepressant. Similarly, in some embodiments, atherapeutic method provided herein comprises the administration of anantidepressant, such as utilizing a formulation or composition describedherein. In certain instances, antidepressants are classified into threefamilies: monoamine oxidase inhibitors (MAOIs), tricyclics and selectiveserotonin reuptake inhibitors (SSRIs). In general, SSRIs work byreducing serotonin reabsorption by the presynaptic neuron. Thus, moreserotonin remains in the synaptic gap for a longer period of time,compensating for the lower levels of serotonin, SSRIs generally havefewer side effects than MAOIs or tricyclics. Notably, SSRIs typicallyonly block the serotonin reuptake pumps, unlike the tricyclics, whichalso block the norepinephrine reuptake pumps. Generally, they do,however, indirectly affect norepinephrine, as norepinephrine levels areclosely linked with those of serotonin; raising serotonin levelsautomatically raises norepinephrine levels.

Examples of selective serotonin reuptake inhibitors include, by way ofnon-limiting example, fluoxetine (PROZAC®), citalopram (CELEXA®),fluvoxamine (LUVOX®), sertraline (ZOLOFT®), and paroxetine (PAXIL®).

In certain embodiments, described herein are pharmaceuticalcompositions, comprising 5HT receptor agonist, or pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof,such agents being collectively referred to herein as 5HT receptoragonist agents. In some instances, the pharmaceutical compositions orformulations of 5HT receptor agonist, or pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof, have enhancedbioavailability and efficacy, have a lower administration dose, a lowercytotoxicity, and/or have decreased side effects.

METHODS OF TREATMENT

Provided herein are methods for managing disorders or conditions, andtreating symptoms of disorders or conditions, comprising administeringone or more 5HT receptor agonists, or pharmaceutically acceptable salts,solvates, metabolites, derivatives, or prodrugs thereof. The methodsprovide improved dosage and administration, enabling enhancedbioavailability and efficacy to subjects in need thereof.

Further provided herein are methods of managing neurological conditionsor the symptoms thereof in a subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising atherapeutically effective amount of one or more 5HT receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof and a pharmaceutically acceptable excipient.

Further provided herein are methods of treating the symptoms of aneurological condition in a subject suffering from the neurologicalcondition, comprising administering to the subject a pharmaceuticalcomposition comprising a therapeutically effective amount of one or more5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof and a pharmaceuticallyacceptable excipient.

Further provided herein are methods of treating the symptoms of aneurological condition in a subject susceptible to the neurologicalcondition, comprising administering to the subject a pharmaceuticalcomposition comprising a therapeutically effective amount of one or more5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof and a pharmaceuticallyacceptable excipient.

Further provided herein are methods for managing neurological disordersor conditions, comprising administering one or more 5HT receptoragonists, or pharmaceutically acceptable salts, solvates, metabolites,derivatives, or prodrugs thereof. Further provided herein are methodsfor treating the symptoms of neurological disorders or conditions,comprising administering one or more 5HT receptor agonists, orpharmaceutically acceptable salts, solvates, metabolites, derivatives,or prodrugs thereof.

Further provided herein are methods of managing neurological conditionsor the symptoms thereof in a subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising atherapeutically effective amount of one or more 5HT2 receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof and a pharmaceutically acceptable excipient.

Further provided herein are methods wherein 5HT receptor agonist is a5HT2 receptor agonist. Further provided herein are methods wherein the5HT2 receptor agonist is a 5HT_(2A) receptor agonist, a 5HT2B receptoragonist and/or a 5HT2C receptor agonist.

In some embodiments, any suitable dosage of 5HT receptor agonist may beadministered to an individual in need thereof, such as about 0.1 mg toabout 10 mg or about 10 mg to about 50 mg is administered. In certainembodiments, the 5HT receptor agonist is administered in a dosage formthat provides at least some release of active over a period of at least12 hours, at least 24 hours, at least 48 hours, at least 72 hours, atleast 96 hours, or any suitable or desirous time period.

Further provided herein are methods wherein the 5HT receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is present in an amount of from about 0.1 mg to about 50mg (e.g. about 0.1 mg to about 10 mg, about 0.2 mg to about 5 mg, about10 mg to about 50 mg, or the like). Further provided herein are methodswherein the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof is present in anamount of about 10 mg. Further provided herein are methods wherein the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is present in an amount ofabout 20 mg. Further provided herein are methods wherein the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is present in an amount ofabout 30 mg. Further provided herein are methods wherein the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is present in an amount ofabout 40 mg. Further provided herein are methods wherein the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is present in an amount ofabout 50 mg.

Further provided herein are methods wherein the therapeuticallyeffective amount of the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof isprovided to the subject in need thereof in an amount insufficient toprovide an adverse side effect, such as hallucinogenic experience.

Further provided herein are methods wherein the therapeuticallyeffective amount of 5HT receptor agonist (e.g. psilocybin) or apharmaceutically acceptable salt, solvate, metabolite (e.g. psilocin, anactive metabolite of psilocybin), derivative, or prodrug thereof isprovided to a subject in need thereof in an amount and/or formulation toprovide a maximum plasma concentration (C_(max)) of (e.g. active form ofthe) 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof of about 0.1 ng/mLor more and less than 6 ng/mL (e.g. at least 0.5 ng/mL and less than 6ng/mL, about 1 ng/mL to about 5.5 ng/mL, about 2 ng/mL to about 5 ng/mL,or the like).

In some embodiments, a method provided herein comprises providing a 5HTreceptor agonist (e.g. in a sufficient dosage and suitable formulation)to provide a minimum therapeutic concentration of (e.g. active form ofthe) 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof for at least 12hours, at least 24 hours, at least 36 hours, at least 48 hours, at least72 hours, at least 96 hours, or the like.

In various embodiments provided herein, 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is administered in any suitable frequency. In someinstances, administration is daily, every other day, about twice a week,at least three times a week (e.g. five days on and two days off), or onany suitable schedule.

In some embodiments, also disclosed herein is a method of managing aneurological condition or one or more symptoms thereof in a subject inneed thereof, comprising administering to the subject a pharmaceuticalcomposition comprising: a) a therapeutically effective amount of one ormore 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof; and b) apharmaceutically acceptable excipient; wherein the therapeuticallyeffective amount of the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof isprovided to the subject in need thereof in an amount insufficient toprovide an adverse side effect, such as hallucinogenic experience.

In some embodiments, also disclosed herein is a method of treating thesymptoms of a neurological condition in a subject suffering from orsusceptible to the neurological condition, comprising administering tothe subject a pharmaceutical composition comprising: a) atherapeutically effective amount of one or more 5HT receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof; and b) a pharmaceutically acceptable excipient; whereinthe therapeutically effective amount of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is provided to the subject in need thereof in an amountinsufficient to provide an adverse side effect, such as hallucinogenicexperience.

In some embodiments, the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ispresent in an amount of from about 0.1 mg to about 50 mg (e.g. about 0.1mg to about 10 mg, about 0.2 mg to about 5 mg, about 10 mg to about 50mg, or the like). In some embodiments, the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is present in an amount of from about 0.1 mg to about 2mg. In some embodiments, the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ispresent in an amount of from about 1 mg to about 15 mg. In someembodiments, the pharmaceutical composition is a low-dose pharmaceuticalcomposition. In some embodiments, the pharmaceutical compositioncomprises a controlled release component. In some embodiments, thepharmaceutical composition comprises a controlled release component andan immediate release component.

In some embodiments, the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of 6 ng/mL or more. In someembodiments, the therapeutically effective amount of 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof is provided to a subject in need thereofin an amount and/or formulation to provide a maximum plasmaconcentration (C_(max)) of (e.g. active form of the) 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof of about 0.1 ng/mL or more and less than6 ng/mL (e.g. at least 0.5 ng/mL and less than 6 ng/mL, about 1 ng/mL toabout 5.5 ng/mL, about 2 ng/mL to about 5 ng/mL, or the like). In someembodiments, the therapeutically effective amount of 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof is provided to a subject in need thereofin an amount and/or formulation to provide a plasma concentration of(e.g. active form of the) 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ofat least 0.1 ng/mL (e.g. at least 0.2 ng/mL, at least 0.3 ng/mL, atleast 0.5 ng/mL, or the like) after at least 6 hours (e.g. at least 12hours, at least 24 hours, at least 36 hours, at least 48 hours, at least72 hours, at least 96 hours, at least 120 hours, at least 144 hours, orthe like).

In some embodiments, the 5HT receptor agonist is a 5HT2 receptoragonist. In some embodiments, the 5HT receptor agonist is psilocybin ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof. In some embodiments, the 5HT receptor agonist ispsilocin or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof.

In some embodiments, the pharmaceutical composition further comprisesone or more agents selected from the group consisting of surfactants,preservatives, flavoring agents, sweetening agents, and antifoamingagents. In some embodiments, the pharmaceutical composition is an oralformulation, a buccal formulation, a nasal formulation, or an inhalationformulation. In some embodiments, the pharmaceutical composition is in aform selected from a spray, aerosol, mist, nebulae, ointment, cream,gel, paste, salve, solution, suspension, tincture, patch, and atomizedvapor.

In some embodiments, the pharmaceutical composition further comprises aneffective amount of a second agent. In some embodiments, the secondagent is a vasodilator or vasoconstrictor. In some embodiments, thevasoconstrictor is epinephrine, phenylephrine, methoxamine,norepinephrine, zolmitriptan, tetrahydrozaline, naphazoline, orcombinations thereof. In some embodiments, the second agent is astimulant, an antihistamine, an antiemetic, an antidepressant, ananti-inflammatory, a growth factor, a lithium compound, resveratrol,phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone,ginseng, lysergic acid diethylamide, or combinations thereof. In someembodiments, the second agent is a 5HT receptor antagonist. In someembodiments, the second agent is an anti-psychotic agent. In someembodiments, the anti-psychotic agent is olanzapine, clozapine,risperidone, paliperidone, aripiprazole, quetiapine, iloperidone,ziprasidone, asenapine, lurasidone, sertindole, amisulpride, clotiapine,mosapramine, perospirone, sulpiride, zotepine, haloperidol, benperidol,loxapine, molindone, pimozide, thioridazine, mesoridazine, thiothixene,chlorprothixene, fluphenazine, trifluoperazine, chlorpromazine,perphenazine, prochlorperazine, droperidol, and zuclopenthixol. In someembodiments, the second agent is a norepinephrine modulator, an alphaadrenergic agonist (e.g. clonidine), a beta adrenergic antagonists (e.g.propranolol), or any combination thereof. In some embodiments, thesecond agent is administered simultaneously, sequentially, oralternately with the pharmaceutical composition. In some embodiments,the second agent is administered simultaneously, sequentially, oralternately with the pharmaceutical composition.

In some embodiments, the pharmaceutical composition is administeredfirst and the second agent is administered at least once before thepharmaceutical composition is administered a subsequent time. In someembodiments, the pharmaceutical composition is administered first andthe second agent is administered more than once before thepharmaceutical composition is administered a subsequent time. In someembodiments, the pharmaceutical composition is administered to a subjectin need thereof no more frequently than once a day (e.g. no morefrequently than once every other day, no more frequently than once everythird day, no more frequently than twice a week, no more frequently thanonce a week, no more frequently than once every two weeks, or the like).In some embodiments, the pharmaceutical composition is administered to asubject in need thereof once a day, every alternate day, three times aweek, twice a week, once a week, every other week, two weeks per month,three weeks per month, once a month, twice a month or three times permonth. In some embodiments, the pharmaceutical composition isadministered about once a day. In some embodiments, the pharmaceuticalcomposition is administered about every alternate day. In someembodiments, the pharmaceutical composition is administered about once aweek. In some embodiments, the pharmaceutical composition isadministered about once every two weeks or more. In some embodiments,the pharmaceutical composition is administered for at least 1 month, 2months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, 18 months, 2 years, or 3 years.

In some embodiments, the neurological condition is a neurologicaldisorder. In some embodiments, the neurological condition is aneurocognitive disorder. In some embodiments, the symptoms of theneurological condition are physical, behavioral, emotional, mental or acombination thereof. In some embodiments, the neurological condition isan addictive disorder. In some embodiments, the addictive disorder isalcohol abuse, substance abuse, smoking, or obesity. In someembodiments, the neurological condition is an eating disorder or anauditory disorder. In some embodiments, the neurological condition ispain (e.g. chronic pain). In some embodiments, the neurologicalcondition is depression, bipolar disorder, anxiety, social anxiety,post-traumatic stress disorder (PTSD), panic disorder, phobia,schizophrenia, psychopathy, or antisocial personality disorder. In someembodiments, the neurological condition is an impulsive disorder. Insome embodiments, the impulsive disorder is attention deficithyperactivity disorder (ADHD), attention deficit disorder (ADD),Tourette's syndrome or autism. In some embodiments, the neurologicalcondition is a compulsive disorder. In some embodiments, the compulsivedisorder is obsessive compulsive disorder (OCD), gambling, or aberrantsexual behavior. In some embodiments, the neurological condition is apersonality disorder. In some embodiments, the personality disorder isconduct disorder, antisocial personality, or aggressive behavior.

Oral Formulations

in some embodiments, described herein are compositions and formulationscomprising a 5HT receptor agonist active ingredient. In someembodiments, the formulation comprising 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof, has an enhanced bioavailability and efficacy, has alower administration dose, a lower cytotoxicity, and has decreased sideeffects.

In some embodiments, the composition or formulation is an oralformulation. In some instances, the oral formulation comprising 5HTreceptor agonist, or pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof, has an enhancedbioavailability and efficacy, has a lower administration dose, a lowercytotoxicity, and has decreased side effects.

In some embodiments, the pharmaceutically acceptable excipient isselected from the group consisting of fillers, binders, suspendingagents, disintegrants, lubricants, and combinations thereof.

In some embodiments, the composition or formulation (e.g. oralcomposition or formulation) comprises a filler. In some embodiments, theamount of the filler is from about 10% to about 20% by weight. In someembodiments, the amount of the filler is from about 10% to about 40% byweight. In some embodiments, the amount of the filler is from about 20%to about 40% by weight. In some embodiments, the amount the filler isabout 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14%w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w,about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28%w/w, about 29% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about33% w/w, about 34% w/w, about 35% w/w, about 36% w/w, about 37% w/w,about 38% w/w, about 39% w/w, or about 40% w/w.

In some embodiments, the composition or formulation (e.g. oralcomposition or formulation) comprises a binder. In some embodiments, theamount of the binder is from about 5% to about 15% by weight. In someembodiments, the amount of the binder is from about 5% to about 25% byweight. In some embodiments, the amount of the binder is from about 15%to about 25% by weight. In some embodiments, the amount of the binder isabout 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w,about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14%w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w,about 24% w/w, or about 25% w/w.

In some embodiments, the composition or formulation (e.g. oralcomposition or formulation) comprises a suspending agent. In someembodiments, the amount of the suspending agent is from about 2% toabout 3% by weight. In some embodiments, the amount of the suspendingagent is from about 2% to about 4% by weight. In some embodiments, theamount of the suspending agent is from about 1% to about 5% by weight.In some embodiments, the amount of the suspending agent is about 1% w/w,about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9%w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8%w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7%w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6%w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w.

In some embodiments, the composition or formulation (e.g. oralcomposition or formulation) comprises a disintegrant. In someembodiments, the amount of the disintegrant is from about 2% to about 3%by weight. In some embodiments, the amount of the disintegrant is fromabout 2% to about 4% by weight. In some embodiments, the amount of thedisintegrant is from about 1% to about 5% by weight. In someembodiments, the amount of the disintegrant is about 1% w/w, about 1.1%w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w,about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2%w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w,about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w,about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w,about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w.

In some embodiments, the composition or formulation (e.g. oralcomposition or formulation) comprises a lubricant. In some embodiments,the amount of the lubricant is from about 2% to about 3% by weight. Insome embodiments, the amount of the lubricant is from about 2% to about4% by weight. In some embodiments, the amount of the lubricant t is fromabout 1% to about 5% by weight. In some embodiments, the amount of thelubricant is about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3%w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w,about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w, about 2.2%w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w,about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w, about 3.1%w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w,about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4%w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w,about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about4.9% w/w, or about 5% w/w.

In some embodiments, the composition or formulation (e.g. oralcomposition or formulation) comprises a surfactant. In some embodiments,the amount of the surfactant is from about 0.1% to about 2% by weight.In some embodiments, the amount of the surfactant is from about 0.1% toabout 5% by weight. In some embodiments, the amount of the surfactant isfrom about 1% to about 15% by weight. In some embodiments, the amount ofthe surfactant is about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w,about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1% w/w,about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5% w/w, about2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3% w/w,about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w, about3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about 3.9%w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about4.4% w/w, about 4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8%w/w, about 4.9% w/w, about 5%, about 6%, about 7%, about 8%, about 9%,about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%.

In some embodiments, the amount of the surfactant is from about 0.5% toabout 5% by weight. In some embodiments, the amount of the surfactant isabout 0.5% by weight. In some embodiments, the amount of the surfactantis about 1% by weight. In some embodiments, the amount of the surfactantis about 2% by weight. In some embodiments, the amount the surfactant isabout 3% by weight. In some embodiments, the amount of the surfactant isabout 4% by weight. In some embodiments, the amount of the surfactant isfrom about 7% to about 15% by weight. In some embodiments, the amount ofthe surfactant is from about 0.5% to about 2% by weight.

Bi-Layer Formulations

In some embodiments, the composition or formulation is or comprises abi-layer formulation (e.g. oral dosage form). In some instances, thebi-layer formulation comprising 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof, has an enhanced bioavailability and efficacy, has alower administration dose, a lower cytotoxicity, and/or has decreasedside effects.

In some embodiments, the bi-layer formulation is an oral dosage formcomprising an (e.g. immediate release or controlled release) top layeror coating and a controlled release core, such as wherein at least oneof (i) the top layer or coating, or (ii) the controlled release corecomprise a 5HT (e.g. 5HT₂) receptor agonist. In specific instances, the(e.g. immediate release or controlled release) top layer or coating andthe controlled release core both comprise a 5HT (e.g. 5HT₂) receptoragonist, the core and coating 5HT receptor agonist being the same ordifferent. Additional agents are contemplated in either or both the (i)top layer or coating and (ii) the core, such as any additional agentdescribed herein (e.g. stimulant, an antihistamine, an antiemetic, anantidepressant, an anti-inflammatory, a growth factor, a lithiumcompound, resveratrol, phosphatidylcholine, curcumin, magnesium,melatonin, pregnenolone, ginseng, tryptophan, lysergic aciddiethylamide, a 5HT receptor antagonist, or any combination thereof).

Controlled Release Coating Formulations

In some embodiments, at least one (e.g. controlled-release) coating(e.g. at least partially, or wholly) surrounds the core of the oraldosage form. In certain embodiments the controlled release coating is astable controlled release monolithic coating that is formed by a processthat comprises coating the core with a coating composition to form acoated core with an intermediate coating, and curing the coated core toform the stable controlled release coating. In at least one embodimentthe coating composition comprises an aqueous dispersion of a neutralester copolymer without any functional groups, a poly-glycol having amelting point of at least 55° C., and one or more secondpharmaceutically acceptable excipients. In some instances, the curing isconducted at a temperature at least equal to or greater than the meltingpoint of the poly-glycol. In at least one embodiment the stablecontrolled release coating comprises a neutral ester copolymer withoutany functional groups, a poly-glycol having a melting point of at least55° C., and one or more second pharmaceutically acceptable excipients.

In certain embodiments, a coating composition (e.g. utilized to form acoating) comprises an aqueous dispersion of a neutral ester copolymerwithout any functional groups. In some embodiments, the aqueousdispersion of a neutral ester copolymer without any functional groups isan ethyl acrylate and methyl methacrylate copolymer dispersion.Non-limiting examples of ethyl acrylate and methyl methacrylatecopolymer dispersions include a 30% aqueous dispersion of a neutralcopolymer based on ethyl acrylate and methyl methacrylate (e.g.Eudragit® NE30D), a 40% aqueous dispersion of a neutral copolymer basedon ethyl acrylate and methyl methacrylate (e.g. Eudragit® NE40D),Eudragit® NM30D, Kollicoat® EMM30D, and combinations thereof. In atleast one embodiment the neutral ester copolymer without any functionalgroups used in the controlled release coating composition is Eudragit®NE30D, Eudragit® NE40D, or a mixture thereof. The neutral estercopolymer without any functional groups might be present in certainembodiments in an amount of from about 1% to about 35% by weight of thecoating composition, depending on the therapeutically active agent usedand the controlled release profile desired. In certain embodiments theneutral ester copolymer without any functional groups is present in anamount from about 20% to about 99.5% by dry weight of the coat. In otherembodiments the neutral ester copolymer without any functional groups ispresent in an amount from about 25% to about 60% by dry weight of thecoat. In still other embodiments the neutral ester copolymer without anyfunctional groups is present in an amount from about 37% to about 50% bydry weight of the coat. In some embodiments, the neutral ester copolymerwithout any functional groups is present in an amount of about 38%,about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about45%, about 46%, about 47%, about 48%, and about 49% by dry weight of thecoat. In certain embodiments, the neutral ester copolymer without anyfunctional groups is present in the coating composition in an amount offrom about 0.4% to about 39.8% by dry weight of the tablet. In otherembodiments in an amount of from about 0.8% to about 24% by dry weightof the tablet. In some other embodiments, the neutral ester copolymerwithout any functional groups is present in the coating composition inan amount of from about 2% to about 5.5% by dry weight of the tablet,for example, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%,about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%,about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%,about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%,about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%,about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4% by dry weightof the tablet.

In some embodiments, the controlled release dosage form does not swellin a dimensionally unrestricted manner upon imbibition of water. Incertain embodiments there is some swelling of the controlled releasedosage form in a dimensionally restricted manner upon imbibition ofwater. In certain embodiments the controlled release coating restrictsthe swelling of the dosage form upon imbibition of water.

In certain embodiments, a coating composition comprises a polyglycol,such as with a melting point of at least about 55° C. In someembodiments, the polyglycol with a melting point of at least about 55°C. is a polyethylene glycol with an average molecular weight rangingfrom about 4,000 Daltons to about 35,000 Daltons. Non-limiting examplesof a polyglycol with a melting point of at least about 55° C. include,by way of non-limiting example, polyethylene glycol 4000, polyethyleneglycol 4600, polyethylene glycol 6000, polyethylene glycol 8000,polyethylene glycol 10000, polyethylene glycol 12000, polyethyleneglycol 20000, polyethylene glycol 35000, or mixtures thereof. In certainembodiments, the polyglycol is selected from the group consisting ofpolyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol10000, polyethylene glycol 12000, and mixtures thereof. In at least oneembodiment the poly-glycol used in the coating composition ispolyethylene glycol 8000. The polyglycol might be present in certainembodiments in an amount of from about 0.1% to about 10% by weight ofthe coating composition. In certain embodiments the poly-glycol ispresent in an amount of from about 0.5% to about 28% by dry weight ofthe coat. In other embodiments the polyglycol is present in an amountfrom about 4% to about 17% by dry weight of the coat. In still otherembodiments the polyglycol is present in an amount from about 7.2% toabout 15.2% by dry weight of the coat, for example, about 7.3%, about7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about9.8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%,about 10.4%, about 10.5%, about 10.6%, about 10.7%, about 10.8%, about10.9%, about 11%, about 11.1%, about 11.2%, about 11.3%, about 11.4%,about 11.5%, about 11.6%, about 11.7%, about 11.8%, about 11.9%, about12%, about 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%,about 12.6%, about 12.7%, about 12.8%, about 12.9%, about 13%, about13.1%, about 13.2%, about 13.3%, about 13.4%, about 13.5%, about 13.6%,about 13.7%, about 13.8%, about 13.9%, about 14%, about 14.1%, about14.2%, about 14.3%, about 14.4%, about 14.5%, about 14.6%, about 14.7%,about 14.8%, about 14.9%, about 15%, and about 15.1% by dry weight ofthe coat. In certain embodiments the poly-glycol is present in thecoating composition in an amount of from about 0.1% to about 11.2% bydry weight of the tablet. In other embodiments the polyglycol is presentin the coating composition in an amount of from about 0.1% to about 8%by dry weight of the tablet. In still other embodiments the polyglycolis present in the coating composition in an amount of from about 0.2% toabout 2.8% by dry weight of the tablet, for example, about 0.3%, about0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, and about 2.7% bydry weight of the tablet. Other suitable polyglycol derivatives having amelting point of at least about 55° C. might be, but are not limited to,Poloxamer 188, Poloxamer 338, Poloxamer 407, polyethylene oxides,polyoxyethylene alkyl ethers, polyoxyethylene stearates, and mixturesthereof.

In addition to the copolymers and the polyglycol, the coatingcomposition optionally comprises one or more other pharmaceuticallyacceptable excipients. The excipients can include, but not limited to,anti-tacking agents, emulsifying agents, antifoaming agents, hydrophilicagents, flavorings, colorants, sweeteners, etc., and any combinationthereof. In some embodiments, excipients might affect the properties ofthe coat in a series of ways, and many substances used in coatformulations might thus be described as multifunctional. A skilledworker will know, based on their technical knowledge, whichpharmaceutically acceptable excipients are suitable for the desiredcontrolled release coating composition.

In some embodiments, hydrophilic agents are included in a composition,formulation, core or coating described herein, such as to promotewetting of the coating when in contact with gastrointestinal fluids.Such hydrophilic agents include, by way of non-limiting example,hydrophilic water soluble polymers such as hydroxypropyl methylcellulose(HPMC) (e.g. Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose(HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethylcellulose, polyvinylpyrrolidone (Povidone® or Kollidon®),polyvinyl alcohol, polyethylene oxide, vinylpyrrolidone-vinyl acetatecopolymer (Kollidon® VA64), polyethylene glycol-polyvinyl alcoholcopolymer (Kollicoat® IR), copolymers thereof, and combinations thereof.In at least one embodiment, HPMC is the hydrophilic agent used in thecoating composition. In certain embodiments, the hydrophilic agentcomprises a pH-dependent polymer, non-limiting examples of whichinclude: cellulose acetate phthalate (e.g. Aquacoat® CPD); celluloseacetate trimellitate, poly(methacrylic acid, ethyl acrylate) 1:1 (e.g.Eudragit® L30D-55); Kollicoat® MAE 30 D; poly(methacrylic acid, ethylacrylate) 1:1 (e.g. Eudragit® L100-55); Kollicoat® MAE 30 DP; Eudragit®FS 30D; Hypromellose Acetate Succinate LF, MF, HF grades (e.g. AQOAT®),polyvinyl acetate phthalate, and mixtures thereof. If hydrophilic agentsare to be included in the coat composition the agents are present in anysuitable amount, such as, in certain embodiments, in an amount fromabout 0.1% to about 10% by weight of the coating composition. In otherembodiments from about 0.1% to about 5% by weight of the coatingcomposition, and in still other embodiments from about 0.1% to about 3%by weight of the coating composition. In certain embodiments thehydrophilic agent is present in an amount of from greater than about 0%to about 35% by dry weight of the coat. In other embodiments thehydrophilic agent is present in an amount from about 8% to about 30% bydry weight of the coat. In still other embodiments the hydrophilic agentis present in an amount from about 12% to about 26% by dry weight of thecoat, for example, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, and about 25% by dry weight of the coat. In certainembodiments the hydrophilic agent is present in the coating formulationin an amount of from about 0% to about 14% by dry weight of the tablet;in other embodiments in an amount of from about 0.2% to about 6% by dryweight of the tablet; and in still other embodiments in an amount offrom about 0.8% to about 2.5% by dry weight of the tablet; for example,about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%,about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%,about 2.1%, about 2.2%, about 2.3%, and about 2.4% by dry weight of thetablet.

In some instances, the tackiness of polymeric films is important for thecoating of dosage forms and for the subsequent curing step (post-coatingthermal treatment). In certain instances, during coating with eithercellulosic or acrylic polymers, an unwanted, and sometimes irreversibleagglomeration of several granules or beads or, in the worst case, of thecomplete batch, might occur, especially at higher product processingtemperatures. Accordingly, in some embodiments, the addition ofanti-tacking agents to coating formulations is desirable. Theanti-tacking agents which are optionally used include but are notlimited to adipic acid, magnesium stearate, calcium stearate, zincstearate, hydrogenated vegetable oils, sterotex, glyceryl monostearate,talc (e.g. Talc 400), sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, and mixtures thereof. In at least one embodiment talc(e.g. talc 400) is used as the anti-tacking agent. In some instances,talc also functions as a wetting agent. In some embodiments, mixtures ofthe anti-tacking agents are utilized. Any suitable amount ofanti-tacking agent is utilized in the coating composition, such fromabout 1% to about 15% by weight of the coating dispersion, and incertain embodiments from about 1% to about 7% by weight of the coatingdispersion. In certain embodiments the anti-tacking agent is present inan amount of from greater than about 0% to about 50% by dry weight ofthe coating. In other embodiments the anti-tacking agent is present inan amount from about 2% to about 40% by dry weight of the coating. Instill other embodiments the anti-tacking agent is present in an amountfrom about 10% to about 30% by dry weight of the coating; for example,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, about 25%, about 26%, about 27%, about 28%, and about 29% bydry weight of the coating. In certain embodiments the anti-tacking agentis present in the coating formulation in an amount of from about 0% toabout 20% by dry weight of the tablet; in other embodiments in an amountof from about 0% to about 12% by dry weight of the tablet; and in stillother embodiments in an amount of from about 0.6% to about 7% by dryweight of the tablet; for example, about 0.7%, about 0.8%, about 0.9%,about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%,about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%,about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%,about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%,about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%,about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%,about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%,about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%,about 5.8%, about 5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%,about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, and about6.9% by dry weight of the tablet.

In certain embodiments, a composition, formulation, core or coatingdescribed herein comprises an anti-foaming agent, such as, by way ofnon-limiting example, silicon oil, simethicone (e.g. simethiconeemulsion), and mixtures thereof. In at least one embodiment theanti-foaming agent is simethicone. The anti-foaming agent, if present,is utilized in any suitable amount, such as in an amount of up to about0.5% by weight of the coat composition, and in certain other embodimentsfrom about 0.1% to about 0.4% by weight of the coating composition. Incertain embodiments the anti-foaming agent is present in an amount offrom greater than about 0% to about 3% by dry weight of the coat. Inother embodiments the anti-foaming agent is present in an amount fromabout 0.4% to about 2% by dry weight of the coat. In still otherembodiments the anti-foaming agent is present in an amount from about0.8% to about 1.5% by dry weight of the coat; for example, about 0.9%,about 1%, about 1.1%, about 1.2%, about 1.3%, and about 1.4% by dryweight of the coat. In certain embodiments the anti-foaming agent ispresent in the coating formulation in an amount of from about 0% toabout 1.2% by dry weight of the tablet; in other embodiments in anamount of from about 0% to about 0.8% by dry weight of the tablet; andin still other embodiments in an amount of from about 0% to about 0.2%by dry weight of the tablet; for example, about 0.01%, about 0.02%,about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%,about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, andabout 0.19% by dry weight of the tablet.

In some embodiments, an emulsifying agent (also called emulsifiers oremulgents) is included in a composition, formulation, core or coatingdescribed herein, such as to facilitate actual emulsification duringmanufacture of the coating, and/or to provide emulsion stability duringthe shelf-life of the product. In some instances, suitable emulsifyingagents include, but are not limited to naturally occurring materials andtheir semi synthetic derivatives, such as the polysaccharides, as wellas glycerol esters, cellulose ethers, sorbitan esters and polysorbates.Mixtures are operable. In at least one embodiment the emulsifying agentused is Polysorbate 80 (polyoxyethylene sorbitan mono-oleate) (e.g.Tween® 80). The emulsifying agent or agents, if present, might bepresent in certain embodiments in an amount of from greater than 0% toabout 0.5% by weight of the coat composition. In at least one embodimentthe emulsifying agent is present in an amount of from about 0.1% toabout 0.3% by weight of the coat composition. In certain embodiments theemulsifying agent is present in an amount of from greater than about 0%to about 2% by dry weight of the coat. In other embodiments theemulsifying agent is present in an amount from about 0.1% to about 1% bydry weight of the coat. In still other embodiments the emulsifying agentis present in an amount from about 0.25% to about 0.75% by dry weight ofthe coat; for example, including about 0.30%, about 0.35%, about 0.40%,about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, andabout 0.70% by dry weight of the coat. In certain embodiments theemulsifying agent is present in the coating formulation in an amount offrom greater than about 0% to about 0.8% by dry weight of the tablet; inother embodiments in an amount of from greater than about 0% to about0.4% by dry weight of the tablet; and in still other embodiments in anamount of from greater than about 0% to about 0.2% by dry weight of thetablet; for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%,about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%,about 0.16%, about 0.17%, about 0.18%, and about 0.19% by dry weight ofthe tablet.

In certain embodiments, a coloring agent is utilized, such as in acoating described herein. In some instances, the colorants is awater-insoluble color (pigments). In some instances, pigments havecertain advantages over water-soluble colors in that they tend to bemore chemically stable towards light, provide better opacity andcovering power, and optimize the impermeability of a given film to watervapor. Examples of suitable colorants include, but are not limited toiron oxide pigments, titanium dioxide, and Aluminum Lakes. Mixtures areoperable. In at least one embodiment the pigment or colorant used istitanium dioxide. The pigment or colorant, if present, might be presentin certain embodiments in an amount of from about 0.1% to about 10% byweight of the coat composition. In at least one embodiment the colorantis present in an amount of from about 0.1% to about 5% by weight of thecoat composition. In at least one other embodiment the colorant ispresent in an amount of from about 0.1% to about 2% by weight of thecoat composition. In certain embodiments the colorant is present in anamount of from greater than about 0% to about 20% by dry weight of thecoat. In other embodiments the colorant is present in an amount fromgreater than about 0% to about 10% by dry weight of the coat. In stillother embodiments the colorant is present in an amount from about 2.2%to about 6.2% by dry weight of the coat; for example, including about2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about5.9%, about 6%, and about 6.1% by dry weight of the coat. In certainembodiments the colorant is present in the coating formulation in anamount of from greater than about 0% to about 8% by dry weight of thetablet; in other embodiments in an amount of from greater than about 0%to about 5% by dry weight of the tablet; and in still other embodimentsin an amount of from greater than about 0% to about 1% by dry weight ofthe tablet; for example, including about 0.1%, about 0.2%, about 0.3%,about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, and about0.9% by dry weight of the tablet.

In certain embodiments, a composition, formulation, core or coatingdescribed herein comprises a first and a second pharmaceuticallyacceptable excipient. In at least one embodiment the secondpharmaceutically acceptable excipients (e.g. in the controlled releasecoating) comprises at least one of a neutral ester copolymer without anyfunctional groups (e.g. Eudragit® NE30D, Eudragit® NE40D, Eudragit®NM30D, Kollicoat® EMM30D, or a mixture thereof), HPMC (e.g.Pharmacoat®606), talc (e.g. Talc 400), polyethylene glycol (e.g.polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethyleneglycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, or amixture thereof), simethicone, Polysorbate 80, titanium dioxide, andmixtures thereof.

In at least one embodiment, a composition, formulation, core or coatingdescribed herein (e.g. a stable controlled release coating) hydrateswhen placed into water. In at least one embodiment the dosage form (e.g.that is coated with the controlled release coating) floats in water. Inat least one embodiment, the (e.g. controlled release) dosage form, uponoral administration to a patient, provides controlled release of aneffective amount of the active drug to at least one region of thepatient's upper gastrointestinal tract (e.g. the stomach).

In some embodiments, any composition, formulation, core or coatingdescribed herein (e.g. controlled release coating) is formed by aprocess that does not involve the use of an organic solvent. In suchembodiments the controlled release coating composition is aqueous-basedand not solvent-based (termed “AQ” in certain examples of dosage formscoated with the aqueous-based controlled release coating). In someembodiments, the composition, formulation, core or coating describedherein (e.g. controlled release coating) is formed by a process that aresolvent based (e.g. “PharmaPASS™” composition).

In various embodiments, a coating composition is applied onto a corecomprising an effective amount of the therapeutically active agent by aprocess, the process comprising atomizating (spraying) the coatingcomposition (solution or suspension) onto a bed of the tablet cores.Some examples of equipment suitable for film coating include: ACCELACOTA® (Manesty Machines, Liverpool, UK), HI-COATER® (Freund Company,Japan), DRIACOATER™ (Driam Metallprodukt GmbH, Germany), HTF/150™ (GS,Italy), and IDA™ (Dumoulin, France). Examples of units that function ona fluidized-bed principle include: AEROMATIC™ (Fielder, Switzerland andUK) and GLATT AG™ (Switzerland). In at least one embodiment theapparatus used is the ACCELA COTA®.

In some instances, coating composition is delivered to the coatingapparatus from a peristaltic pump at the desired rate and sprayed ontothe rotating or fluidizing tablet cores. The tablet cores are pre-warmedto about 30° C. During the coating process, the product temperaturerange is maintained between about 25° C. and about 35° C. by adjustingthe flow rate of the inlet and outlet air, temperature of the inlet airand spray rate. A single layer of the coating composition is applied andonce spraying is complete, the coated tablet cores are dried betweenabout 30° C. to about 40° C. for about 3 to about 5 minutes at a low panspeed and low air flow. The pan is readjusted to jog speed, and dryingcontinued for about 12 to about 15 minutes.

In certain embodiments, coated tablet cores are placed onto a tray andcured (post coating thermal treatment) in an electrical or steam oven ata temperature above the temperature of the melting point of thepolyethylene glycol or derivative thereof. In at least one embodimentthe curing temperature is greater than the melting point of thepolyethylene glycol or derivative thereof. In at least one embodimentthe curing time is from about 2 to about 7 hours. The cured coatedtablets are subsequently cooled to about room temperature.

In certain other embodiments, the coated tablet cores are placed onto acoating pan and cured at two-stages. During the first stage, the coatedtablets are cured at a first curing temperature (for example, in certainembodiments from between about 50° C. to about 59° C.) for a period oftime (for example, in certain embodiments from about 15 minutes to about90 minutes; and in at least one embodiment for about 60 minutes). Duringthe second stage, the coated tablets are cured at a second curingtemperature that is at least equal to or greater than the melting pointof the poly-glycol (for example, in certain embodiments from betweenabout 60° C. to about 70° C.) for an additional period of time (forexample, in certain embodiments from about 30 minutes to about 180minutes; and in at least one embodiment for about 120 minutes). In atleast one embodiment the two-stage curing of the coated tablets reducesnon-functional defects on the tablet caused by the curing process. In atleast one embodiment the two-stage curing process substantiallyeliminates non-functional defects on the tablet caused by the curingprocess. Non-functional defects on the dosage form caused by the curingprocess can include visual defects in the coating (e.g. poor coloruniformity, and/or dull appearance), defects in the surface of thecoating (e.g. roughness in the surface of the coating, and/or wrinklesin the coating), and sticking of the tablets to each other and/or to thecoating pan. In addition, the reduced defects in color and smoothness ofthe tablets allows for improved printing of the tablets

In some embodiments, the coating formulation is used to coat a varietyof 5HT receptor agonist cores and might be adjusted to obtain a desireddrug release profile. The length and time for the delay is controlled byrate of hydration and the thickness of the coat. The drug release ratesubsequent to the delay is determined by the thickness and permeabilityof the hydrated coat. Thus, it is possible to regulate the rate ofhydration and permeability of the coat so that the desired controlledrelease drug profile might be achieved. There is no preferred coatthickness, as this will depend on the drug being used in the core andalso the controlled release profile desired. Other parameters incombination with the thickness of the coat include varying theconcentrations of some of the ingredients of the stable coat compositionand/or varying the curing temperature and length of curing the coatedtablet cores. The skilled artisan will know which parameters orcombination of parameters to change for a desired controlled releaseprofile.

Immediate-Release Coating Formulations

In some embodiments, a composition or formulation (e.g. oral dosageform) provided herein comprises an immediate-release coating (e.g.providing immediate release of a 5HT receptor agonist). In someembodiments, the immediate-release coating comprises 5HT receptoragonist. In some embodiments, the immediate-release coating comprisesmore than one 5HT receptor agonist. In further embodiments, theimmediate release coating comprises a pharmaceutically acceptableexcipient. In some embodiments, the immediate release coating comprisesa 5HT receptor agonist and an additional (e.g. pharmaceutically active)agent. In other embodiments, the immediate release coating comprises anadditional (e.g. pharmaceutically active) agent, but not a 5HT receptoragonist. In some embodiments, the additional agent reduces, abates oreliminates adverse side effects associated with administration of the5HT receptor agonist. In some embodiments, the additional agent thatreduces, abates or eliminates adverse side effects associated withadministration of the 5HT receptor agonist, is a 5HT receptorantagonist. In some embodiments, the additional agent in the immediaterelease coating is a 5HT receptor antagonist. In some embodiments, theadditional agent in the immediate release coating is selected from thegroup selected from a stimulant, an antihistamine, an antiemetic, anantidepressant, an anti-inflammatory, a growth factor, a lithiumcompound, resveratrol, phosphatidylcholine, curcumin, magnesium,melatonin, pregnenolone, ginseng, tryptophan, lysergic aciddiethylamide, or a 5HT receptor antagonist, and combinations thereof.

In some embodiments, an (e.g. therapeutically) effective amount of theimmediate release active agent in immediate release form is coated ontothe formulations described herein. For example, in some instances wherethe extended release of a 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereoffrom the formulation is due to a controlled release coating, theimmediate release layer of the additional agent would be overcoated ontop of the controlled release coating. In some embodiments, theimmediate release layer of the additional agent is coated onto thesurface of substrates wherein the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is incorporated in a controlled release matrix. Where aplurality of the sustained release substrates comprising an effectiveunit dose of the 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof (e.g.multiparficulate systems including pellets, spheres, beads and the like)are incorporated into a hard gelatin capsule, the side effect-reducingcompound might be incorporated into the gelatin capsule via inclusion ofthe sufficient amount of immediate release antihistamine or antiemeticas a powder or granulate within the capsule. Alternatively, the gelatincapsule itself is optionally coated with an immediate release layer ofthe additional agent.

A coating containing the immediate release comprising an additionalagent such as antihistamine or antiemetic is optionally added to theoutside of a (e.g. controlled release tablet core, such as comprising a5HT receptor agonist described herein) to produce a final dosage form.Such a coating is prepared by any suitable method, such as beingprepared by mixing compounds like promethazine with polyvinylpyrrolidone(PVP) 29/32 or hydroxypropyl methylcellulose (HPMC) and water/isopropylalcohol and triethyl acetate. Such an immediate-release coating isoptionally spray coated onto the tablet cores. The immediate-releasecoating is, in some instances, applied using a press-coating processwith a blend consisting of 80% by weight promethazine and 20% by weightof lactose and hydroxypropyl methylcellulose type 2910.

In some embodiments, a composition or formulation provided herein (e.g.a formulation comprising an immediate release component and a controlledrelease component) is in the form of a bi-layered tablet, such ascomprising a first layer and a second layer. In some embodiments, thefirst layer is an immediate release layer and/or the second layer is acontrolled release layer. The first (or top) or immediate release layercomprises a first active agent, such as a 5HT receptor agonist and/oranother agent, such as an agent selected from analgesics, antitussives,antihistamines, antiemetics, and stimulants. In some instances, thesecond or controlled release layer comprises a second drug, such as a5HT receptor agonist. In some embodiments, the second drug is 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof. In some embodiments, thesecond drug is a formulation of 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof described herein. The bi-layered tablet provides aplasma concentration within the therapeutic range of the second drugover a period which is coextensive with at least about 70% of the period(i.e. 12 hours) within which the bi-layered tablet provides a plasmaconcentration within the therapeutic range of the first drug.

In some embodiments, a coating or layer (e.g. an immediate release orcontrolled release coating or layer) described herein comprises astimulant. In some embodiments, the stimulant is selected from the groupconsisting of aminophylline, caffeine, dyphlline, oxitriphylline,theophylline, amphetamine, benzphetamine, dextroamphetamine,diethylpropion, mazindol, methamphetamine, methylphenidate,dexmethylphenidate, pemoline, sibutramine, modafinil, atomoxetine,phendimetrizine, phenteramine, adrafinil, phenylpropanolamine,psuedoephedrine, synephrine, amphetaminil, furfenorex, or a combinationthereof.

In some embodiments, a coating or layer (e.g. an immediate release orcontrolled release coating or layer) comprises an antiemetic. In someembodiments, the antiemetic is selected from the group consisting ofaprepitant, dronabinol, perphenazine, palonosetron, trimethobenzamide,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, droperidol, haloperidol, prochloperazine,metoclopramide, diphenhydramine, cannabis, midazolam, lorazepam,hyoscine, dexamethasone, emetrol, propofol, or a combination thereof.

In some embodiments, a coating or layer (e.g. an immediate release orcontrolled release coating or layer) comprises an antihistamine. In someembodiments, the antihistamine is selected from the group consisting of2-(m-fluorophenyl)-histamine, chlorpheniramine, mepyramine, terfenadine,astemizole, triprolidine, ethanolamines carbinoxamine, diphenhydramine,doxylamine, pyrilamine, tripelennamine, hydroxyzine, fexofenadine,brompheniramine chlorpheniramine, cyproheptadine, loratadine,cetirizine, dimaprit, impromidine, amthamine, cimetidine, ranitidine,nizatidine, famotidine, R-alpha-methylhistamine, imetit, immepip,thioperamide, iodophenpropit, clobenpropit, clobenpropit, imetit,clozapine, thioperamide, azelastine, brompheniramine, carbinoxamine,cetrizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine,desloratidine, dimenhydrinate, diphenhydramine, emedastine,fexofenadine, ketotifen, levocabastine, loratadine, meclizine,olopatadine, phenindamine, promethazine, or a combination thereof.

In some embodiments, a coating or layer (e.g. immediate release orcontrolled release coating or layer) comprises an antidepressant. Insome embodiments, the antidepressant is selected from the groupconsisting of Abilify (aripiprazole), Adapin (doxepin), Anafranil(clomipramine), Aplenzin (bupropion), Asendin (amoxapine), Aventyl HCI(nortriptyline), Celexa (citalopram), Cymbalta (duloxetine), Desyrel(trazodone). Effexor XR (venlafaxine), Emsam (selegiline), Etrafon(perphenazine and amitriptyline), Elavil (amitriptyline), Endep(amitriptyline), Fetzima (levomilnacipran), Khedezla (desvenlafaxine),Latuda (lurasidone), Lamictal (lamotrigine), Lexapro (escitalopram),Limbitrol (amitriptyline and chlordiazepoxide), Marplan (isocarboxazid),Nardil (phenelzine), Norpramin (desipramine), Oleptro (trazodone),Pamelor (nortriptyline), Parnate (tranylcypromine), Paxil (paroxetine),Pexeva (paroxetine); Prozac (fluoxetine), Pristiq (desvenlafaxine),Remeron (mirtazapine), Sarafem (fluoxetine), Seroquel XR (quetiapine),Serzone (nefazodone), Sinequan (doxepin), Surmontil (trimipramine),Symbyax (fluoxetine and the atypical antipsychotic drug olanzapine),Tofranil (imipramine), Triavil (perphenazine and amitriptyline),Trintelllix (vortioxetine), Viibryd (vilazodone), Vivactil(protriptyline), Wellbutrin (bupropion), Zoloft (sertraline), andZyprexa (olanzapine).

In some embodiments, a coating or layer (e.g. immediate release orcontrolled release coating or layer) comprises an anti-inflammatory. Insome embodiments, the anti-inflammatory is selected from the groupconsisting of Aceclofenac, Aspirin, Celecoxib, Diclofenac, DiflunisalEtodolac, Etoricoxib, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin,Ketoprofen, Ketorolac, Lornoxicam, Loxoprofen, Mefenamic acid,Meloxicam, Montelukast, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone,Piroxicam, Pranlukast, Salsalate, Sulindac, Tenoxicam, Tiaprofenic acid,Tolmetin, Valdecoxib, Zafirlukast. and Zileuton.

In some embodiments, a coating or layer (e.g. immediate release orcontrolled release coating or layer) comprises a growth factor. In someembodiments, the growth factor is selected from the group consisting ofPlatelet-Derived Growth Factor (PDGF), Transforming Growth Factor β(TGF-β), Epidermal Growth Factor (EGF), Vascular Endothelial GrowthFactor (VEGF), Insulin-like Growth Factor (IGF), basic Fibroblast GrowthFactor (bFGF).

In some embodiments, a coating or layer (e.g, immediate release layer)comprises a lithium compound, such as lithium carbonate, lithiumcitrate, or lithium orotate.

Controlled Release Matrix Formulations

In some embodiments, provided herein is a controlled release formulationor composition (e.g. an oral dosage form, or a core of an oral dosageform, or a layer of an oral dosage form, such as a tablet). In certainembodiments, the controlled release formulation or composition is coatedor layered with another composition or formulation. In some instances,the controlled release formulation or composition is coated or layeredwith an immediate and/or controlled release coating or layer, such asdescribed herein. In specific embodiments, a controlled releasecomposition or formulation provided herein comprises a 5HT receptoragonist formulation comprising a controlled release matrix and (e.g,from about 0.1 to about 50 mg, about 10 mg to about 50 mg, about 0.1 mgto about 10 mg, about 0.2 mg to about 5 mg, or about 0.1 mg to about 2mg, or about 1 mg to about 15 mg) of a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof. In some embodiments, the controlled and/or immediaterelease coating or layer comprises a first active agent, such as a 5HTagonist and/or another agent, such as an agent selected from analgesics,antitussives, antihistamines, antiemetics, and stimulants. In certainembodiments, the coating (e.g. controlled release and/or immediaterelease coating) comprises any suitable agent, such as a stimulant, anantihistamine, an antiemetic, an antidepressant, an anti-inflammatory, agrowth factor, a lithium compound, resveratrol, phosphatidylcholine,curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan,lysergic acid diethylamide, and a 5HT receptor antagonist. In someembodiments, the coating (e.g. controlled release and/or immediaterelease coating) comprises a 5HT receptor agonist, such as describedherein and a second agent, such as, by way of non-limiting example, astimulant, an antihistamine, an antiemetic, an antidepressant, ananti-inflammatory, a growth factor, a lithium compound, resveratrol,phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone,ginseng, tryptophan, lysergic acid diethylamide, a 5HT receptorantagonist or any combination thereof

Controlled Release Matrix

Active agents are released from a controlled release matrix in anysuitable manner. Two exemplary mechanisms of release of the activeagent(s) from a controlled release matrix include diffusion and/ordegradation. Generally, diffusion occurs when the bioactive agent isreleased either through pores in the polymer matrix or by passingbetween polymer chains of the matrix. Typically, in a diffusion system,the bioactive agent might be dispersed throughout the matrix, orlocalized within a reservoir adjacent to or within the matrix. In someembodiments, the controlled release formulation utilizes a reservoirsystem, which typically comprises a reservoir of bioactive agent, forexample, solid drug, dilute solution, or highly concentrated drugsolution within a polymer matrix is surrounded by a controlled releasematerial through which the bioactive agent is able to diffuse.Generally, in a degradable system, the bioactive agent is released asthe matrix is degraded in vivo. In some instances, bioactive agent isreleased by a combination of such mechanisms. In some embodiment of thecontrolled release matrix described herein, the release of the bioactiveagent is driven by a combination of both diffusion and degradation. Incertain instances, the release rate is controlled by varying the drug topolymer ratio (e.g. a higher drug concentration tends to result in afaster rate of release) and/or by varying the chemistry of polymericmatrix (e.g. inclusion of polymers having a glass transition temperature(Tg) of less than about 40° C. or less than about 0° C. would tend toresult in a faster elution rate than polymers with Tgs greater than 40°C., polymers that absorb water tend to elute drug more quickly than morehydrophobic polymers that do not absorb water). In some instances, thesevariables are controlled by the selection of materials used in themanufacturing process.

In some embodiments, the controlled release matrix is configured torelease at least about 40% and up to about 60%, or at least 50% of thebioactive agent within 24 hours of administration. In anotherembodiment, the controlled release matrix is configured to release atleast about 80% or up to about 100%, or at least 90% of the bioactiveagent within 7 days after administration.

In some embodiments, the controlled release matrix is biodegradable. Insome embodiments, the controlled release matrix includes a biodegradablepolyester. Examples of biodegradable polyesters include, but are notlimited to: polycaprolactone (PCL), polylactic acid (PLA), polyglycolide(PGA), and copolymers thereof, such as poly(lactic-co-glycolic acid)polymers (PLGA) and poly(glycolide-co-caprolactone) (PGC). PCL refers toa biodegradable polyester prepared by ring opening polymerization ofε-caprolactone using a catalyst such as stannous octanoate. PCL has amelting point of about 60° C. and is degraded by hydrolysis of its esterlinkages under physiological conditions. PLA is a biodegradable,thermoplastic polyester that can be produced by bacterial fermentationof renewable resources such as corn, starch or sugarcane and has amelting temperature between about 173° C. and about 178° C. PGA is abiodegradable, thermoplastic polyester prepared from glycolic acid bypolycondensation or ring-opening polymerization. It has a melting pointof between about 225° C. to about 230° C. A PLGA polymer refers to abiodegradable copolymer of lactic and glycolic acid formed by randomring-opening co-polymerization of monomers of glycolic acid and lacticacid. During polymerization, the monomeric units are linked together byester linkages, thus yielding an aliphatic polyester. PLGAs areamorphous and have a glass transition temperature between about 40° C.and 60° C. In general, the PLGA copolymer has a weight average molecularweight between about 1000 Da to about 50,000 Da, or between about 5000Da and 25,000 Da. The ratio of lactic acid to glycolic acid might vary.In general, and increase in the amount of lactic acid results in apolymer that degrades more slowly. An increase in glycolic acid resultsin a polymer that degrades more quickly. Additionally, an increase inglycolic acid tends to decrease the Tg and water penetration into thepolymer, which can result in a faster release of compounds. In general,the ratio of lactic acid to glycolic acid is between about 100:0 toabout 25:75, or between about 60:40 and 40:60, or about 50:50. Othersuitable biodegradable polymers include, but are not limited to,poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), and poly(butylene succinate) (PBS), poly(trimethylenecarbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),and poly(butylene succinate) (PBS). In some embodiments, the polymericmaterial or polymer is biostable. Examples of biostable polymersinclude, but are not limited to polyurethanes, silicone rubbers,styrene-isobutylene-styrene block copolymers, ether-ester blockcopolymers (e.g. RTP 1500-40D from RTP Co.) and vinyl materials,including but not limited to poly(ethylene-co-vinyl acetate) (PEVA). Insome embodiments, the controlled release matrix includes an elastomericpolymeric material that includes a copolymer with an elastomeric (or“soft”) component and a non-elastomeric (or “hard”) component. Inanother embodiment, the elastomeric polymeric material includes apolymeric blend having an elastomeric component and a non-elastomericcomponent. In some embodiments, the compliant polymer or polymericmaterial is thermoplastic. As used herein, the term “thermoplastic”refers to a polymer or polymeric material that can be softened by heat,hardened by cooling and then softened by heat over and over again. Ingeneral, thermoplastic materials are not cross-linked. However, inanother embodiment, the compliant polymer or polymeric material might becross-linked.

The bioactive agent is incorporated into the controlled release matrix,if used, using any suitable technique, such as any of various techniquesknown to the skilled artisan. In one embodiment, the bioactive agent isdispersed throughout the controlled release matrix. Techniques forpreparing the controlled release matrix include, but are not limited to,melt extrusion processes, injection molding, or spray casting. In atypical melt extrusion process, a mixture that includes the polymericmaterial and bioactive agent is combined in an extruder, heated to atemperature at which the polymeric material melts and then dischargedthrough an orifice of the desired cross-sectional shape. The extrudedmaterial is collected under controlled conditions (e.g. speed,temperature and humidity) to obtain a product with the desireddimensions. In one embodiment, the mass flow rate of the extrudate andthe collection speed of the final extruded form might be controlled toachieve the desired physical dimensions. For example, if the finalextruded form is a film, then the collection speed of the film might beincreased relative to the mass flow rate of the extrudate to decreasethe film thickness, and conversely to increase the film thickness. Theextrudate is discharged through an orifice in the molten state, allowingelongation of the extrudate to its final dimension. The extrudate issubsequently cooled by exposure to ambient conditions, a chilled liquidor gas bath, or exposure to a temperature controlled surface such as acooled roller in order to solidify the extrudate. In one embodiment, themelt extrusion process is used to form a film. In an alternateembodiment, the melt extrusion process is used to form pellets or beadsthat might be subsequently molded into the desired film or collarconfiguration. Some of the advantages of melt extrusion processesinclude: the absence of organic solvents and high throughput, continuousmanufacturing. In general, the processing temperature is sufficient tomelt the polymeric material without adversely affecting the biologicalactivity of the bioactive agent. In general, the processing temperatureis at least about 80° C. or about 100° C., and less than about 180° C.,less than 160° C., or between about 110° C. and about 150° C. In someembodiments, the specific temperature is dependent on the melting anddegradation temperatures of the polymeric materials and bioactive agent.Furthermore, melt-processing provides the ability for continuousoperation, the ability to control operating parameters, and the abilityto scale up manufacturing. In an alternate embodiment, an injectionmolding process is used. In a typical injection molding process, amixture that includes the polymeric material and bioactive agent is fedinto a vessel where it heated to a temperature sufficient to melt thepolymeric material and then forced into a mold cavity where it cools andhardens to the configuration of the mold cavity. The conditions (e.g.temperature and pressure) will depend upon the material being molded. Inone embodiment, the injection molding process is used to form a film ora collar. In yet another embodiment, a solvent casting technique isused. In a typical solvent casting process, the polymeric material andbioactive agent are combined with a suitable solvent to form a polymericsolution which is then cast on a substrate. The solvent is then removedto form a film, for example, by evaporation. In one embodiment, thesolvent is removed under a vacuum (e.g. between about 15 in Hg and about28 in Hg, depending upon the volatility of the solvent). In anotherembodiment, the solvent is removed at an elevated temperature (e.g.between about 30° C. and about 80° C.). In an alternate embodiment, thepolymeric solution is applied to the substrate by a spray coatingprocess. In a spray coating process, the polymeric solution is fed tothe spray nozzle, for example and ultrasonic spray nozzle, at acontrolled rate by a positive displacement pump. The spray nozzle andsubstrate are moved in relative motion to each other at controlled speedto achieve the desired coating thickness. The spray nozzle is mounted ona three-axis motion control system (x-y-z) which is capable ofcontrolling the speed and position of the spray head relative to thesubstrate. In addition, if the substrate is a rolled film, it istraversed below the spray head by a roll to roll unwinding and windingapparatus. The coating width is controlled by moving the spray nozzle ina specified path across the width of the substrate. In addition, theheight (z) of the spray nozzle above the substrate might be increased toachieve a wider coating width. In some instances, solvent forms a truesolution with the components therein. In certain instances, thebioactive agent is soluble in the solvent or form a dispersion withinthe solvent. Any suitable solvents is optionally used, such as, by wayof non-limiting example, alcohols (e.g. methanol, butanol, propanol andisopropanol), alkanes (e.g. halogenated or unhalogenated alkanes such ashexane, cyclohexane, methylene chloride and chloroform), amides (e.g.dimethylformamide), ethers (e.g. tetrahydrofuran (THF), dioxolane, anddioxane), ketones (e.g. methyl ethyl ketone, acetone), aromaticcompounds (e.g. toluene and xylene), nitriles (e.g. acetonitrile) andesters (e.g. ethyl acetate). THF and chloroform have been found to besuitable solvents due to their excellent solvency for a variety ofpolymers and bioactive agents.

Mucoadhesive Agents

Often, mucoadhesive drug delivery systems interact with the mucus layercovering the mucosal epithelial surface to increase the residence timeof the dosage form at the site of absorption. In some instances, acomposition or formulation provided herein comprises a mucoadhesiveagent, such as, by way of non-limiting example, a soluble PVP, acarbopol, a crosslinked poly(acrylic acid) (e.g. Carbopol 974P), acarbomer homopolymer, a carbomer copolymer, a water-swellable, butwater-insoluble, fibrous, cross-linked carboxy-functional polymer, amucoadhesive polysaccharide (e.g. a hydrophilic polysaccharide gum), oneor more maltodextrin, alginate, a cross-linked aliginate gum gel, awater-dispersible polycarboxylated vinyl polymer. In some embodiments,the mucoadhesive agent is a carbopol. In some embodiments, themucoadhesive agent is selected from, by way of non-limiting example,Carbopol 974P, Carbopol Ultrez 10, sodium alginate LF120 and sodiumalginate H120L. In some embodiments, the mucoadhesive agent is acellulose. In specific embodiments, the mucoadhesive agent is acarboxymethyl-cellulose (CMC), e.g. sodium carboxymethyl-cellulose(NaCMC), microcrystalline cellulose (MCC), or a combination thereof. Inone non-limiting example, the mucoadhesive agent is a combination of MCCand CMC (e.g. Avicel RC-591). In some embodiments, the CMC/MCCcombination (e.g. Avicel® RC-591) is present in the composition in anamount of about 1 mg/mL to about 150 mg/mL, 1 mg/mL to about 75 mg/mL,or about 5 mg/mL to about 40 mg/mL. In certain embodiments, the CMC/MCCmixed weight ratio is between about 1/99 and about 99/1, about 20/80 andabout 5/95, or about 15/85 and about 10/90. In a specific embodiment,the CMC is NaCMC and the CMC/MCC mixed weight ratio is about 11/89.

In some embodiments, a mucoadhesive drug delivery system is acomposition comprising both a CMC (e.g. a CMC/MCC mixture) andmaltodextrin. In certain embodiments, the combination of a CMC (e.g. aCMC/MCC mixture) and maltodextrin provide an increased residence time onan afflicted or targeted surface of the mucosa (e.g. gastrointestinaltract), when compared to a composition having a similar amount of eitherthe CMC (e.g. a CMC/MCC mixture) or maltodextrin alone.

In some embodiments, a pharmaceutical composition, formulation, and/ordosage form of a 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof disclosedherein, comprises a mucoadhesive agent. In some embodiments, themucoadhesive agent comprises one or more maltodextrin. In variousaspects, the physical characteristics of maltodextrins vary depending,e.g. on the dextrose equivalent of the specific maltodextrin. In someembodiments, the dextrose equivalent of a specific maltodextrin mightaffect the viscosity, hygroscopicity, sweetness, humectancy, plasticity,solubility and or mucoadhesiveness of the maltodextrin. In someembodiments, a maltodextrin is selected based on the specific characterthat is desired to be imparted upon the pharmaceutical compositiondescribed herein. In some embodiments, a maltodextrin is selected thatincreases the mucoadhesive character of a composition described hereinwithout substantially increasing the viscosity of the composition (e.g.compared to an otherwise identical composition lacking themaltodextrin). In some embodiments, the oral pharmaceutical compositioncomprises a second inaltodextrin that increases the viscosity of theoral pharmaceutical composition (e.g. compared to an otherwise identicalcomposition lacking the second maltodextrin). In some embodiments, thesecond maltodextrin that does not substantially affect the mucoadhesivecharacteristic of the pharmaceutical composition (e.g. compared to anotherwise identical composition lacking the second maltodextrin).

In some embodiments, the mucoadhesive agent does not substantiallyincrease the viscosity of the oral pharmaceutical composition (e.g.compared to an otherwise identical composition lacking the mucoadhesiveagent). In some embodiments, the mucoadhesive agent is chosen for itsmucoadhesive properties (e.g. its ability to impart mucoadhesivecharacter upon the oral pharmaceutical composition).

In some embodiments, a mucoadhesive agent utilized in an oralpharmaceutical composition described herein imparts an increasedviscosity upon the oral pharmaceutical composition (e.g. compared to anotherwise identical composition lacking the mucoadhesive agent). Inother embodiments, the mucoadhesive agent does not substantiallyincrease the viscosity of the oral pharmaceutical composition (e.g.compared to an otherwise identical composition lacking the mucoadhesiveagent).

In some embodiments, at least one mucoadhesive agent is chosen for andused in the pharmaceutical composition so the addition of the at leastone mucoadhesive agent does not substantially increase the viscosity ofthe resulting oral pharmaceutical composition (e.g. compared to anotherwise identical composition lacking the mucoadhesive agent).

In some embodiments, at least two mucoadhesive agents are chosen for andused in the pharmaceutical composition so the addition of the at leasttwo mucoadhesive agents do not substantially increase the viscosity ofthe resulting oral pharmaceutical composition (e.g. compared to anotherwise identical composition lacking the mucoadhesive agents). Insome embodiments, at least one mucoadhesive agent, if taken alone in thepharmaceutical composition would increase the viscosity of thepharmaceutical composition, but taken together with all components inthe pharmaceutical composition, does not substantially increase theviscosity of the resulting oral pharmaceutical composition (e.g.compared to an otherwise identical composition lacking the at least onemucoadhesive agent).

In some embodiments, the viscosity of the composition is at least about2 centipoise (cP), at least about 5 cP, at least about 10 cP, at leastabout 20 cP, at least about 25 cP, at least about 35 cP, at least about40 cP, at least about 50 cP, at least about 200 cP, or at least about225 cP. In some embodiments, the viscosity of the composition is atleast about 100 cP. In certain embodiments, the viscosity of thecomposition, measured at 25° C., is about 50 cP to about 250,000 cP,about 50 cP to about 70,000 cP, about 50 cP to about 25,000 cP, about 50cP to about 10,000 cP, about 50 cP to about 3,000 cP, or about 50 cP toabout 2,000 cP. In one aspect, the viscosity of the composition, asmeasured at 25° C., is from about 25 centipoise (cP) to about 800 cP,about 50 cP to about 800, or about 300 cP to about 800 cP (e.g. measuredby a Brookfield viscometer). In another aspect, the viscosity of thecomposition might range from about 100 cP to about 200 cP, about 200 cPto about 300 cP, about 250 cP to about 600 cP or about 400 cP to about600 cP. In specific embodiments, the viscosity of the formulation isabout 30 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP,about 500 cP, or about 250,000 cP (e.g. as measured with a Brookfieldviscometer at 25° C.).

In certain embodiments, provided herein is a composition having aviscosity that is at least about 2 centipoise (cP), at least about 5 cP,at least about 10 cP, at least about 20 cP, at least about 25 cP, atleast about 30 cP, at least about 35 cP, at least about 40 cP, at leastabout 50 cP, at least about 200 cP, at least about 225 cP, at leastabout 250 cP, at least about 300 cP, or at least about 400 cP. In someembodiments, the viscosity of the composition under such conditions isabout 50 cP to about 250,000 cP, about 50 cP to about 70,000 cP, about50 cP to about 25,000 cP, about 50 cP to about 10,000 cP, about 50 cP toabout 3,000 cP, about 50 cP to about 2,000 cP, about 250 cP to about250,000 cP, about 250 cP to about 70,000 cP, about 250 cP to about25,000 cP, about 250 cP to about 10,000 cP, about 250 cP to about 3,000cP, or about 250 cP to about 2,000 cP. In one aspect, the viscosity ofthe composition, as measured at 25 degrees Celsius, is from about 25centipoise (cP) to about 800 cP, about 50 cP to about 800, or about 300cP to about 800 cP (e.g. measured by a Brookfield viscometer). Inanother aspect, the viscosity of the composition under such conditionsmight range from about 100 cP to about 200 cP, about 200 cP to about 300cP, about 250 cP to about 600 cP or about 400 cP to about 600 cP. Inspecific embodiments, the viscosity of the formulation measured undersuch conditions is about 30 cP, about 40 cP, about 100 cP, about 200 cP,about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP.

In one non-limiting example, a mucoadhesive agent can be, by way ofnon-limiting example, at least two particulate components selected fromtitanium dioxide, silicon dioxide, and clay. In some embodiments, whenthe composition is not further diluted with any liquid prior toadministration, the level of silicon dioxide is from about 3% to about15%, by weight of the composition. In certain embodiments, silicondioxide is selected from, by way of non-limiting example, fumed silicondioxide, precipitated silicon dioxide, coacervated silicon dioxide, gelsilicon dioxide, and mixtures thereof. In some embodiments, clay isselected from, by way of non-limiting example, kaolin minerals,serpentine minerals, smectites, illite or mixtures thereof. In certainembodiments, clay is selected from, by way of non-limiting example,laponite, bentonite, hectorite, saponite, montmorillonites or mixturesthereof.

In some embodiments, the mucoadhesive agent is selected in an amountsufficient to cause the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereofcontaining pharmaceutical composition to adhere to or resides upon asurface of the mucous membrane for 5 seconds, 10 seconds, 15 seconds, 30seconds, 45 seconds, or 1 minute following application to the surface ofthe mucous membrane. In certain embodiments, the mucoadhesive agent isselected in an amount sufficient to cause the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof containing composition to adhere to or reside upon thesurface of the mucous membrane for 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes after application to thesurface of the mucous membrane. In some embodiments, the amount of 51-1Treceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof containing composition thatadheres to a surface of the mucous membrane for 5 seconds, 10 seconds,or 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,3:5, 40, 45, 50, 55 or 60 minutes is at least 1%, at least 2%, at least3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, atleast 9%, at least 10%, at least 15%, at least 20%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90% or at least 95% by weight after administration to the surfaceof the mucous membrane. In specific embodiments, at least 50% of thepharmaceutical composition adheres to or resides upon the surface of themucous membrane for at least 1 or at least 15 minutes followingapplication to the surface of the mucous membrane.

Optional viscosity-enhancing excipients used in pharmaceuticalcompositions described herein include, by way of non-limiting example, acrosslinked poly(acrylic acid) (e.g. Carbopol 974P), glycerin, acarbomer homopolymer, a carbomer copolymer, acacia (gum arabic), agar,aluminum magnesium silicate, sodium alginate, sodium stearate,bladderwrack, bentonite, carbomer, carrageenan, Carbopol, cellulose,microcrystalline cellulose (MCC), ceratonia, chondrus, dextrose,furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose,maltodextrin, mannitol, sorbitol, honey, maize starch, wheat starch,rice starch, potato starch, gelatin, sterculia gum, xanthum gum,polyethylene glycol (e.g. PEG 200-4500) gum tragacanth, ethyl cellulose,ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,polygeline, povidone, propylene carbonate, methyl vinyl ether/maleicanhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate),poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose,hydroxypropylmethyl-cellulose, carboxymethyl-cellulose (CMC) (including,e.g. sodium carboxymethyl-cellulose (NaCMC)), silicon dioxide, PVP(Povidone), Splenda® (dextrose, maltodextrin and sucralose) orcombinations thereof.

Excipients

In certain embodiments, one or more compositions or formulations of a5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof described above furthercomprise an excipient. In some embodiments, aqueous suspensions of thepharmaceutical composition disclosed herein contain pharmaceuticallyacceptable excipients, such as a suspending agent (e.g. methylcellulose), a wetting agent (e.g. lecithin, lysolecithin and/or along-chain fatty alcohol), as well as coloring agents, preservatives,flavoring agents, and the like.

Pharmaceutical preparations for oral use are obtained using any suitableprocess, such as by combining active with a solid excipient, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in some instances, fillers suchas sugars, including lactose, sucrose, mannitol, or sorbitol; flavoringelements, cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or PVP. If desired, disintegrating agentsmight be added, such as the cross-linked PVP, agar, or alginic acid or asalt thereof such as sodium alginate. The active compounds might also beformulated as a sustained release preparation.

Pharmaceutical preparations that are optionally used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules might contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds might be dissolved or suspended insuitable liquids, such as fatty oils, liquid paraffin, or liquidpolyethylene glycols. In addition, stabilizers might be added. Allformulations for oral administration should be in dosages suitable foradministration.

For injection, the pharmaceutical compositions disclosed herein areoptionally formulated in aqueous solutions, preferably inphysiologically compatible buffers such as Hank's solution, Ringer'ssolution, or physiological saline buffer. Such compositions might alsoinclude one or more excipients, for example, preservatives,solubilizers, fillers, lubricants, stabilizers, albumin, and the like.Methods of formulation are known in the art, for example, as disclosedin Remington's Pharmaceutical Sciences, latest edition, Mack PublishingCo., Easton, Pa. These pharmaceutical compositions might also beformulated for transmucosal administration, buccal administration, foradministration by inhalation, for parental administration, fortransdermal administration, and rectal administration.

In addition to the disclosed formulations, the pharmaceuticalcompositions are optionally formulated as a depot preparation. Such longacting formulations might be administered by implantation ortranscutaneous delivery (for example subcutaneously or intramuscularly),intramuscular injection or use of a transdermal patch. Thus, forexample, the pharmaceutical compositions are optionally formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

In some embodiments, the pharmaceutical formulations include, but arenot limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate-release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations (e.g. nanoparticleformulations), and mixed immediate and controlled release formulations.

In some instances, the pharmaceutical formulation includesmultiparticulate formulations. In some instances, the pharmaceuticalformulation includes nanoparticle formulations. In some instances,nanoparticles comprise cyclodextrins or lipids. In some cases,nanoparticles comprise solid lipid nanoparticles, polymericnanoparticles, self-emulsifying nanoparticles, liposomes,microemulsions, or micellar solutions.

In some instances, a nanoparticle includes a core or a core and a shell,as in a core-shell nanoparticle.

In some instances, a nanoparticle is further coated with molecules forattachment of functional elements. In some instances, a coatingcomprises chondroitin sulfate, dextran sulfate, carboxymethyl dextran,alginic acid, pectin, carragheenan, fucoidan, agaropectin, porphyran,karaya gum, gellan gum, xanthan gum, hyaluronic acids, glucosamine,galactosamine, chitin (or chitosan), polyglutamic acid, polyasparticacid, lysozyme, cytochrome C, ribonuclease, trypsinogen,chymotrypsinogen, α-chymotrypsin, polylysine, polyarginine, histone,protamine, ovalbumin or dextrin or cyclodextrin.

In some cases, a nanoparticle has at least one dimension of less thanabout 500 nm, 400 nm, 300 nm, 200 nm, or 100 nm.

In some embodiments, the pharmaceutical formulations include a carrieror carrier materials selected on the basis of compatibility with thecomposition disclosed herein, and the release profile properties of thedesired dosage form. Pharmaceutically compatible carrier materialsinclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerin, magnesium silicate, PVP, cholesterol, cholesterol esters,sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine,sodium chloride, tricalcium phosphate, dipotassium phosphate, celluloseand cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and any combinationthereof. See, e.g. Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

In some instances, the pharmaceutical formulations further include pHadjusting agents or buffering agents which include acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

In some instances, the pharmaceutical formulation includes one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

In some instances, the pharmaceutical formulations include binder whichare used to hold a 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof and inactiveingredients together in a cohesive mix. Suitable binders include, butare not limited to, carboxymethylcellulose, methylcellulose (e.g.Methocel®), hydroxypropylmethylcellulose Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.Klucel®), ethylcellulose (e.g. Ethocel®), and microcrystalline cellulose(e.g. Avicel®), microcrystalline dextrose, amylose, magnesium aluminumsilicate, polysaccharide acids, bentonites, gelatin, PVP/vinyl acetatecopolymer, crospovidone, povidone, starch, pregelatinized starch,tragacanth, dextrin, a sugar, such as sucrose (e.g. Dipac®), glucose,dextrose, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab®),lactose, a natural or synthetic gum such as acacia, tragacanth, ghattigum, mucilage of isapol husks, starch, PVP (e.g. Povidone® CL, Kollidon®CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan,Veegum®, polyethylene glycol, waxes, sodium alginate, and anycombination thereof.

In some instances, the pharmaceutical formulations further includediluent which are used to stabilize a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof because they provide a more stable environment. Saltsdissolved in buffered solutions (which also provide pH control ormaintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution. In certain instances,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g. lactose, starch, mannitol, sorbitol, dextrose;microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and any combination thereof.

In some cases, the pharmaceutical formulations include disintegrationagents or disintegrants to facilitate the breakup or disintegration of asubstance. The term “disintegrate” includes both the dissolution anddispersion of the dosage form when contacted with gastrointestinalfluid. Examples of disintegration agents include a starch, e.g. anatural starch such as corn starch or potato starch, a pregelatinizedstarch such as National 1551 or Amijel®, or sodium starch glycolate suchas Promogel® or Explotab®, a cellulose such as a wood product,methylcrystalline cellulose, e.g. Avicel®, Avicel® PH101, Avicel® PH102,Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose, a cross-linked starch such as sodium starch glycolate, across-linked polymer such as crospovidone, a cross-linked PVP, alginatesuch as alginic acid or a salt of alginic acid such as sodium alginate,a clay such as Veegum® HV (magnesium aluminum silicate), a gum such asagar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and any combination thereof.

In some instances, the pharmaceutical formulations include fillingagents such as lactose, calcium carbonate, calcium phosphate, dibasiccalcium phosphate, calcium sulfate, microcrystalline cellulose,cellulose powder, dextrose, dextrates, dextran, starches, pregelatinizedstarch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulosephthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS),sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,polyethylene glycol, and any combination thereof.

Lubricants and glidants are also optionally included in thepharmaceutical formulations disclosed herein for preventing, reducing orinhibiting adhesion or friction of materials. Exemplary lubricantsinclude, e.g. stearic acid, calcium hydroxide, talc, sodium stearylfumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetableoil such as hydrogenated soybean oil (Sterotex®), higher fatty acids andtheir alkali-metal and alkaline earth metal salts, such as aluminum,calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol,talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate,sodium chloride, leucine, a polyethylene glycol (e.g. PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, starchsuch as corn starch, silicone oil, a surfactant, and any combinationthereof.

Plasticizers include compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g. PEGs such as PEG 300, PEG 400, PEG 600, PEG1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid,triethyl cellulose and triacetin. Plasticizers also function asdispersing agents or wetting agents.

Solubilizers include compounds such as triacetin, triethylcitrate, ethyloleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, PVP, hydroxypropylmethyl cellulose,hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol,cholesterol, bile salts, polyethylene glycol 200-600, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide and anycombination thereof.

Stabilizers include compounds such as any antioxidation agents, buffers,acids, preservatives and any combination thereof.

Suspending agents include compounds such as PVP, e.g. PVP K12, PVP K17,PVP K25, or PVP K30, vinyl pyrrolidone/vinyl acetate copolymer (S630),PEG, e.g. the PEG has a molecular weight of about 300 to about 6000, orabout 3350 to about 4000, or about 7000 to about 5400, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,hydroxymethylcellulose acetate stearate, Polysorbate 80,hydroxyethylcellulose, sodium alginate, gums, such as, e.g. gumtragacanth and gum acacia, guar gum, xanthans, including xanthan gum,sugars, cellulosics, such as, e.g. sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, Polysorbate 80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone, and any combination thereof.

Surfactants include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g. Pluronic® (BASF), and any combinationthereof. Additional surfactants include polyoxyethylene fatty acidglycerides and vegetable oils, e.g. polyoxyethylene (60) hydrogenatedcastor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g.octoxynol 10, octoxynol 40. Sometimes, surfactants are included toenhance physical stability or for other purposes.

Viscosity enhancing agents include, e.g. methyl cellulose, xanthan gum,carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethyl cellulose acetate stearate,hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol,alginates, acacia, chitosans and combinations thereof.

Wetting agents include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts,and any combination thereof.

Antifoaming agents are chemical additive that reduces and hinders theformation of foam in the preparation of an oral liquid formulation. Theterms antifoaming agent and defoamer are often used interchangeably.Commonly used agents are insoluble oils, polydimethylsiloxanes (e.g.simethicone) and other silicones, certain alcohols, stearates andglycols. The additive is used to prevent formation of foam or is addedto break foam already formed. Antifoaming agents reduce foaming in thepreparation of an oral liquid formulation which might result incoagulation of aqueous dispersions. In some embodiments, the 5HTreceptor agonist compositions described herein comprise an antifoamingagent. In some embodiments, the antifoaming agent is simethicone.

In some embodiments, there is a considerable overlap between excipientsused in the pharmaceutical compositions, formulations, and dosage formsof a 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof described herein.Thus, the above-listed additives should be taken as merely exemplary,and not limiting, of the types of additives that might be included insolid dosage forms of the pharmaceutical compositions described herein.

Methods of Pharmaceutical Formulations and Routes of Administration

In some embodiments, 5HT receptor agonists or pharmaceuticalcompositions or formulations described herein are administered to asubject by multiple administration routes, including but not limited to,oral, parenteral (e.g. intravenous, subcutaneous, intramuscular),intranasal, inhalation, buccal, topical, rectal, or transdermaladministration routes. In some embodiments, pharmaceutical compositionsdescribed herein, which include 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof, are formulated into any suitable dosage form, includingbut not limited to, emulsions suitable for injection, nanosuspensionssuitable for injection, aqueous oral dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, aerosols, controlled releaseformulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulates formulations, and mixedimmediate-release and controlled release formulations.

In some embodiments, the pharmaceutical composition for oral use is atablet, (including a suspension tablet, a fast melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g. capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In some embodiments, thepharmaceutical composition for oral use is a solid dosage form, e.g.tablets, effervescent tablets, and capsules. In some embodiments, thesolid dosage forms are prepared by mixing particles of 5HT receptoragonist, or pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof, with one or more pharmaceuticalexcipients to form a bulk blend composition. When referring to thesebulk blend compositions as homogeneous, it is meant that the particlesof 5HT receptor agonist, or pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof, are dispersed evenlythroughout the composition so that the composition might be subdividedinto equally effective unit dosage forms, such as tablets, pills, andcapsules. The individual unit dosages might also include film coatings,which disintegrate upon oral ingestion or upon contact with diluent.

For oral administration, the pharmaceutical compositions disclosedherein are, in some instances, formulated readily by combining theactive compound(s) with pharmaceutically acceptable carriers well knownin the art. Such carriers enable the compositions disclosed herein to beformulated as tablets, including chewable tablets, pills, dragees,capsules, lozenges, hard candy, liquids, gels, syrups, slurries,powders, suspensions, elixirs, wafers, and the like, for oral ingestionby a patient to be treated. Such formulations might comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents.Generally, the compositions disclosed herein will be included atconcentration levels ranging from about 0.5%, about 5%, about 10%, about20%, or about 30% to about 50%, about 60%, about 70%, about 80% or about90% by weight of the total composition of oral dosage forms, in anamount sufficient to provide a desired unit of dosage.

Dosage

In some embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 1 mg/ml toabout 30 mg/ml. In some embodiments, the amount of 5HT receptor agonist,or pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 0.1 mg/mlto about 10 mg/ml. In some embodiments, the amount of 5HT receptoragonist, or pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof used in a pharmaceutical composition isabout 0.1 mg/ml, about 0.2 mg/ml, about 0.3 mg/ml, about 0.4 mg/ml,about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml,about 0.9 mg/ml, about 1 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2 mg/ml, about 2.1 mg/ml,about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml,about 2.6 mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml,about 3 mg/ml, about 3.1 mg/ml, about 3.2 mg/ml, about 3.3 mg/ml, about3.4 mg/ml, about 3.5 mg/ml, about 3.6 mg/ml, about 3.7 mg/ml, about 3.8mg/ml, about 3.9 mg/ml, about 4 mg/ml, about 4.1 mg/ml, about 4.2 mg/ml,about 4.3 mg/ml, about 4.4 mg/ml, about 4.5 mg/ml, about 4.6 mg/ml,about 4.7 mg/ml, about 4.8 mg/ml, about 4.9 mg/ml, about 5 mg/ml, about5.1 mg/ml, about 5.2 mg/ml, about 5.3 mg/ml, about 5.4 mg/ml, about 5.5mg/ml, about 5.6 mg/ml, about 5.7 mg/ml, about 5.8 mg/ml, about 5.9mg/ml, about 6 mg/ml, about 6.1 mg/ml, about 6.2 mg/ml, about 6.3 mg/ml,about 6.4 mg/ml, about 6.5 mg/ml, about 6.6 mg/ml, about 6.7 mg/ml,about 6.8 mg/ml, about 6.9 mg/ml, about 7 mg/ml, about 7.1 mg/ml, about7.2 mg/ml, about 7.3 mg/ml, about 7.4 mg/ml, about 7.5 mg/ml, about 7.6mg/ml, about 7.7 mg/ml, about 7.8 mg/ml, about 7.9 mg/ml, about 8 mg/ml,about 8.1 mg/ml, about 8.2 mg/ml, about 8.3 mg/ml, about 8.4 mg/ml,about 8.5 mg/ml, about 8.6 mg/ml, about 8.7 mg/ml, about 8.8 mg/ml,about 8.9 mg/ml, about 9 mg/ml, about 9.1 mg/ml, about 9.2 mg/ml, about9.3 mg/ml, about 9.4 mg/ml, about 9.5 mg/ml, about 9.6 mg/ml, about 9.7mg/ml, about 9.8 mg/ml, about 9.9 mg/ml, about 10 mg/ml, about 10.1mg/ml, about 10.2 mg/ml, about 10.3 mg/ml, about 10.4 mg/ml, about 10.5mg/ml, about 10.6 mg/ml, about 10.7 mg/ml, about 10.8 mg/ml, about 10.9mg/ml, about 11 mg/ml, about 11.1 mg/ml, about 11.2 mg/ml, about 11.3mg/ml, about 11.4 mg/ml, about 11.5 mg/ml, about 11.6 mg/ml, about 11.7mg/ml, about 11.8 mg/ml, about 11.9 mg/ml, about 12 mg/ml, about 12.1mg/ml, about 12.2 mg/ml, about 12.3 mg/ml, about 12.4 mg/ml, about 12.5mg/ml, about 12.6 mg/ml, about 12.7 mg/ml, about 12.8 mg/ml, about 12.9mg/ml, about 13 mg/ml, about 13.1 mg/ml, about 13.2 mg/ml, about 13.3mg/ml, about 13.4 mg/ml, about 13.5 mg/ml, about 13.6 mg/ml, about 13.7mg/ml, about 13.8 mg/ml, about 13.9 mg/ml, about 14 mg/ml, about 14.1mg/ml, about 14.2 mg/ml, about 14.3 mg/ml, about 14.4 mg/ml, about 14.5mg/ml, about 14.6 mg/ml, about 14.7 mg/ml, about 14.8 mg/ml, about 14.9mg/ml, about 15 mg/ml, about 15.5 mg/ml, about 16 mg/ml, about 16.5mg/ml, about 17 mg/ml, about 17.5 mg/ml, about 18 mg/ml, about 18.5mg/ml, about 19 mg/ml, about 19.5 mg/ml, about 20 mg/ml, about 21 mg/ml,about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml, about27.5 mg/ml, about 30 mg/ml.

In some embodiments, the amount of a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to about0.8 mg/ml to about 24 mg/ml of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in other embodiments, the amount of 5HT receptoragonist, or pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof in the pharmaceutical compositioncorresponds to about 0.8 mg/ml, about 0.9 mg about 1 mg/ml, about 1.1mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, about 1.5mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9mg/ml, about 2 mg/ml, about 2.1 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml,about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2.7 mg/ml,about 2.8 mg/ml, about 2.9 mg/ml, about 3 mg/ml, about 3.1 mg/ml, about3.2 mg/ml, about 3.3 mg/ml, about 3.4 mg/ml, about 3.5 mg/ml, about 3.6mg/ml, about 3.7 mg/ml, about 3.8 mg/ml, about 3.9 about 4 mg/ml, about4.1 mg/ml, about 4.2 mg/ml, about 4.3 mg/ml, about 4.4 mg/ml about 4.5mg/ml, about 4.6 mg/ml, about 4.7 mg/ml, about 4.8 mg/ml, about 4.9mg/ml, about 5 mg/ml, about 5.1 mg/ml, about 5.2 mg/ml, about 5.3 mg/ml,about 5.4 mg/ml, about 5.5 mg/ml, about 5.6 mg/ml, about 5.7 mg/ml,about 5.8 mg/ml, about 5.9 mg/ml, about 6 mg/ml, about 6.1 mg/ml, about6.2 mg/ml, about 6.3 mg/ml, about 6.4 mg/ml, about 6.5 mg/ml, about 6.6mg/ml, about 6.7 mg/ml, about 6.8 mg/ml, about 6.9 mg/ml, about 7 mg/ml,about 7.1 mg/ml, about 7.2 mg/ml, about 7.3 mg/ml, about 7.4 mg/ml,about 7.5 mg/ml, about 7.6 mg/ml, about 7.7 mg/ml, about 7.8 mg/ml,about 7.9 mg/ml, about 8 mg/ml, about 8.1 mg/ml, about 8.2 mg/ml, about8.3 mg/ml, about 8.4 mg/ml, about 8.5 mg/ml, about 8.6 about 8.7 mg/ml,about 8.8 mg/ml, about 8.9 mg/ml, about 9 mg/ml, about 9.1 mg/ml, about9.2 mg/ml, about 9.3 mg/ml, about 9.4 mg/ml, about 9.5 mg/ml, about 9.6mg/ml, about 9.7 mg/ml, about 9.8 mg/ml, about 9.9 mg/ml, about 10mg/ml, about 10.1 mg/ml, about 10.2 mg/ml, about 10.3 mg/ml, about 10.4mg/ml, about 10.5 mg/ml, about 10.6 mg/ml, about 10.7 mg/ml, about 10.8mg/ml, about 10.9 mg/ml, about 11 mg/ml, about 11.1 mg/ml, about 11.2mg/ml, about 11.3 mg/ml, about 11.4 mg/ml, about 11.5 mg/ml, about 11.6mg/ml, about 11.7 mg/ml, about 11.8 mg/ml, about 11.9 mg/ml, about 12mg/ml, about 12.1 mg/ml, about 12.2 about 12.3 mg/ml, about 12.4 mg/ml,about 12.5 mg/ml, about 12.6 mg/ml, about 12.7 mg/ml, about 12.8 mg/ml,about 12.9 mg/ml, about 13 mg/ml, about 13.1 mg/ml, about 13.2 mg/ml,about 13.3 mg/ml, about 13.4 mg/ml, about 13.5 mg/ml, about 13.6 mg/ml,about 13.7 mg/ml, about 13.8 mg/ml, about 13.9 mg/ml, about 14 mg/ml,about 14.1 mg/ml, about 14.2 mg/ml, about 14.3 mg/ml, about 14.4 mg/ml,about 14.5 mg/ml, about 14.6 mg/ml, about 14.7 mg/ml, about 14.8 mg/ml,about 14.9 mg/ml, about 15 mg/ml, about 15.5 mg/ml, about 16 mg/ml;about 16.5 mg/ml, about 17 mg/ml, about 17.5 mg/ml, about 18 mg/ml,about 18.5 mg/ml, about 19 mg/ml, about 19.5 mg/ml, about 20 mg/ml,about 21 mg/ml, about 22 mg/ml, about 23 mg/ml, or about 2.4 mg/ml of a5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

In some embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 0.001 mgto about 20 mg. In some embodiments, the amount of 5HT receptor agonist,or pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 0.005 mgto about 10 mg. In some embodiments, the amount of 5HT receptor agonist,or pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 0.01 mg toabout 5 mg. In some embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 0.05 mg toabout 2.5 mg. In other embodiments, the amount of 5HT receptor agonist,or pharmaceutically acceptable salt, solvate, metabolite, derivative; orprodrug thereof in the pharmaceutical composition corresponds to about0.001 mg, about 0.005 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg,about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg, about0.15 mg, about 0.17 mg, about 0.2 mg, about 0.23 mg, about 0.25 mg,about 0.28 mg, about 0.3 mg, about 0.33 mg, about 0.35 mg, about 0.37mg, about 0.4 mg, about 0.43 mg, about 0.45 mg, about 0.47 mg, about 0.5mg, about 0.53 mg, about 0.55 mg, about 0.57 mg, about 0.6 mg, about0.63 mg, about 0.65 mg, about 0.67 mg, about 0.7 mg, about 0.73 mg,about 0.75 mg, about 0.78 mg, about 0.8 mg, about 0.83 mg, about 0.85mg, about 0.87 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1mg, about 12 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg,about 1.7 mg, about 1.8 about 1.9 mg, about 2 mg, about 2.1 mg, about2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg about 2.6 mg, about 2.7mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg,about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg,about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg,about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg,about 4.8 mg, about 4.9 mg, about 5 mg, about 6 mg, about 7 mg, about 8mg, about 9 mg, about 10 mg, or about 11 mg.

In other embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to no lessthan 0.001 mg, no less than 0.005 mg, no less than 0.01 mg, no less than0.02 mg, no less than 0.03 mg, no less than 0.04 mg, no less than 0.05mg, no less than 0.06 mg, no less than 0.07 mg, no less than 0.08 mg, noless than 0.09 mg, no less than 0.1 mg, no less than 0.11 mg, no lessthan 0.12 mg, no less than 0.15 mg, no less than 0.17 mg, no less than0.2 mg, no less than 0.23 mg, no less than 0.25 mg, no less than 0.28mg, no less than 0.3 mg, no less than 0.33 mg, no less than 0.35 mg, noless than 0.37 mg, no less than 0.4 mg, no less than 0.43 mg, no lessthan 0.45 mg, no less than 0.47 mg, no less than 0.5 mg, no less than0.53 mg, no less than 0.55 mg, no less than 0.57 mg, no less than 0.6mg, no less than 0.63 mg, no less than 0.65 mg, no less than 0.67 mg, noless than 0.7 mg, no less than 0.73 mg, no less than 0.75 mg, no lessthan 0.78 mg, no less than 0.8 mg, no less than 0.83 mg, no less than0.85 mg, no less than 0.87 mg, no less than 0.9 mg, no less than 0.95mg, no less than 1 mg, no less than 1.1 mg, no less than 1.2 mg, no lessthan 1.3 mg, no less than 1.4 mg, no less than 1.5 mg, no less than 1.6mg, no less than 1.7 mg, no less than 1.8 mg, no less than 1.9 mg, noless than 2 mg, no less than 2.1 mg, no less than 2.2 mg, no less than2.3 mg, no less than 2.4 mg, no less than 2.5 mg, no less than 2.6 mg,no less than 2.7 mg, no less than 2.8 mg, no less than 2.9 mg, no lessthan 3 mg, no less than 3.1 mg, no less than 3.2 mg, no less than 3.3mg, no less than 3.4 mg, no less than 3.5 mg, no less than 3.6 mg, noless than 3.7 mg, no less than 3.8 mg, no less than 3.9 mg, no less than4 mg, no less than 4.1 mg, no less than 4.2 mg, no less than 4.3 mg, noless than 4.4 mg, no less than 4.5 mg, no less than 4.6 mg, no less than4.7 mg, no less than 4.8 mg, no less than 4.9 mg, no less than 5 mg, noless than 5.1 mg, no less than 5.2 mg, no less than 5.3 mg, no less than5.4 mg, no less than 5.5 mg, no less than 5.6 mg, no less than 5.7 mg,no less than 5.8 mg, or no less than 5.9 mg.

In other embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to no morethan 0.005 mg, no more than 0.01 mg, no more than 0.02 mg, no more than0.03 mg, no more than 0.04 mg, no more than 0.05 mg, no more than 0.06mg, no more than 0.07 mg, no more than 0.08 mg, no more than 0.09 mg, nomore than 0.1 mg, no more than 0.11 mg, no more than 0.12 mg, no morethan 0.15 mg, no more than 0.17 mg, no more than 0.2 mg, no more than0.23 mg, no more than 0.25 mg, no more than 0.28 mg, no more than 0.3mg, no more than 0.33 mg, no more than 0.35 mg, no more than 0.37 mg, nomore than 0.4 mg, no more than 0.43 mg, no more than 0.45 mg, no morethan 0.47 mg, no more than 0.5 mg, no more than 0.53 mg, no more than0.55 mg, no more than 0.57 mg, no more than 0.6 mg, no more than 0.63mg, no more than 0.65 mg, no more than 0.67 mg, no more than 0.7 mg, nomore than 0.73 mg, no more than 0.75 mg, no more than 0.78 mg, no morethan 0.8 mg, no more than 0.83 mg, no more than 0.85 mg, no more than0.87 mg, no more than 0.9 mg, no more than 0.95 mg, no more than 1 mg,no more than 1.1 mg, no more than 1.2 mg, no more than 1.3 mg, no morethan 1.4 mg, no more than 1.5 mg, no more than 1.6 mg, no more than 1.7mg, no more than 1.8 mg, no more than 1.9 mg, no more than 2 mg, no morethan 2.1 mg, no more than 2.2 mg, no more than 2.3 mg, no more than 2.4mg, no more than 2.5 mg, no more than 2.6 mg, no more than 2.7 mg, nomore than 2.8 mg, no more than 2.9 mg, no more than 3 mg, no more than3.1 mg, no more than 3.2 mg, no more than 3.3 mg, no more than 3.4 mg,no more than 3.5 mg, no more than 3.6 mg, no more than 3.7 mg, no morethan 3.8 mg, no more than 3.9 mg, no more than 4 mg, no more than 4.1mg, no more than 4.2 mg, no more than 4.3 mg, no more than 4.4 mg, nomore than 4.5 mg, no more than 4.6 mg, no more than 4.7 mg, no more than4.8 mg, no more than 4.9 mg, no more than 5 mg, no more than 5.1 mg, nomore than 5.2 mg, no more than 5.3 mg, no more than 5.4 mg, no more than5.5 mg, no more than 5.6 mg, no more than 5.7 mg, no more than 5.8 mg,no more than 5.9 mg, or no more than 6 mg.

In some embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof used in a pharmaceutical composition is about 0.001mg/kg to about 50 mg/kg. In some embodiments, the amount of 5HT receptoragonist, or pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof used in a pharmaceutical composition isabout 0.005 mg/kg to about 10 mg/kg. In some embodiments, the amount of5HT receptor agonist, or pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof used in a pharmaceuticalcomposition is about 0.01 mg/kg to about 5 mg/kg. In some embodiments,the amount of 5HT receptor agonist, or pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof used in apharmaceutical composition is about 0.05 mg/kg to about 1 mg/kg. Inother embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to about0,001 mg/kg, about 0.005 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg,about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg,about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg,about 0.11 mg/kg, about 0.12 mg/kg, about 0.15 mg/kg, about 0.17 mg/kg,about 0.2 mg/kg, about 0.23 mg/kg, about 0.25 mg/kg, about 0.28 mg/kg,about 0.3 mg/kg, about 0.33 mg/kg, about 0.35 mg/kg, about 0.37 mg/kg,about 0.4 mg/kg, about 0.43 mg/kg, about 0.45 mg/kg, about 0.47 mg/kg,about 0.5 mg/kg, about 0.53 mg/kg, about 0.55 mg/kg, about 0.57 mg/kg,about 0.6 mg/kg, about 0.63 mg/kg, about 0.65 mg/kg, about 0.67 mg/kg,about 0.7 mg/kg, about 0.73 mg/kg, about 0.75 mg/kg, about 0.78 mg/kg,about 0.8 mg/kg, about 0.83 mg/kg, about 0.85 mg/kg, about 0.87 mg/kg,about 0.9 mg/kg, about 0.95 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg,about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg,about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg,about 2.9 mg/kg, about 3 mg/kg, about 3.1 mg/kg, about 3.2 mg/kg, about3.3 mg/kg, about 3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg, about 3.7mg/kg, about 3.8 mg/kg, about 3.9 mg/kg, about 4 mg/kg, about 4.1 mg/kg,about 4.2 mg/kg, about 4.3 mg/kg, about 4.4 mg/kg, about 4.5 mg/kg,about 4.6 mg/kg, about 4.7 mg/kg, about 4.8 mg/kg, about 4.9 mg/kg,about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9mg/kg, or about 10 mg/kg.

In other embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to no lessthan 0.001 mg/kg, no less than 0.005 mg/kg, no less than 0.01 mg/kg, noless than 0.02 mg/kg, no less than 0.03 mg/kg, no less than 0.04 mg/kg,no less than 0.05 mg/kg, no less than 0.06 mg/kg, no less than 0.07mg/kg, no less than 0.08 mg/kg, no less than 0.09 mg/kg, no less than0.1 mg/kg, no less than 0.11 mg/kg, no less than 0.12 mg/kg, no lessthan 0.15 mg/kg, no less than 0.17 mg/kg, no less than 0.2 mg/kg, noless than 0.23 mg/kg, no less than 0.25 mg/kg, no less than 0.28 mg/kg,no less than 0.3 mg/kg, no less than 0.33 mg/kg, no less than 0.35mg/kg, no less than 0.37 mg/kg, no less than 0.4 mg/kg, no less than0.43 mg/kg, no less than 0.45 mg/kg, no less than 0.47 mg/kg, no lessthan 0.5 mg/kg, no less than 0.53 mg/kg, no less than 0.55 mg/kg, noless than 0.57 mg/kg, no less than 0.6 mg/kg, no less than 0.63 mg/kg,no less than 0.65 mg/kg, no less than 0.67 mg/kg, no less than 0.7mg/kg, no less than 0.73 mg/kg, no less than 0.75 mg/kg, no less than0.78 mg/kg, no less than 0.8 mg/kg, no less than 0.83 mg/kg, no lessthan 0.85 mg/kg, no less than 0.87 mg/kg, no less than 0.9 mg/kg, noless than 0.95 mg/kg, no less than 1 mg/kg, no less than 1.1 mg/kg, noless than 1.2 mg/kg, no less than 1.3 mg/kg, no less than 1.4 mg/kg, noless than 1.5 mg/kg, no less than 1.6 mg/kg, no less than 1.7 mg/kg, noless than 1.8 mg/kg, no less than 1.9 mg/kg, no less than 2 mg/kg, noless than 2.1 mg/kg, no less than 2.2 mg/kg, no less than 2.3 mg/kg, noless than 2.4 mg/kg, no less than 2.5 mg/kg, no less than 2.6 mg/kg, noless than 2.7 mg/kg, no less than 2.8 mg/kg, no less than 2.9 mg/kg, noless than 3 mg/kg, no less than 3.1 mg/kg, no less than 3.2 mg/kg, noless than 3.3 mg/kg, no less than 3.4 mg/kg, no less than 3.5 mg/kg, noless than 3.6 mg/kg, no less than 3.7 mg/kg, no less than 3.8 mg/kg, noless than 3.9 mg/kg, no less than 4 mg/kg, no less than 4.1 mg/kg, noless than 4.2 mg/kg, no less than 4.3 mg/kg, no less than 4.4 mg/kg, noless than 4.5 mg/kg, no less than 4.6 mg/kg, no less than 4.7 mg/kg, noless than 4.8 mg/kg, no less than 4.9 mg/kg, or no less than 5 mg/kg.

In other embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to no morethan 0.005 mg/kg, no more than 0.01 mg/kg, no more than 0.02 mg/kg, nomore than 0.03 mg/kg, no more than 0.04 mg/kg, no more than 0.05 mg/kg,no more than 0.06 mg/kg, no more than 0.07 mg/kg, no more than 0.08mg/kg, no more than 0.09 mg/kg, no more than 0.1 mg/kg, no more than0.11 mg/kg, no more than 0.12 mg/kg, no more than 0.15 mg/kg, no morethan 0.17 mg/kg, no more than 0.2 mg/kg, no more than 0.23 mg/kg, nomore than 0.25 mg/kg, no more than 0.28 mg/kg, no more than 0.3 mg/kg,no more than 0.33 mg/kg, no more than 0.35 mg/kg, no more than 0.37mg/kg, no more than 0.4 mg/kg, no more than 0.43 mg/kg, no more than0.45 mg/kg, no more than 0.47 mg/kg, no more than 0.5 mg/kg, no morethan 0.53 mg/kg, no more than 0.55 mg/kg, no more than 0.57 mg/kg, nomore than 0.6 mg/kg, no more than 0.63 mg/kg, no more than 0.65 mg/kg,no more than 0.67 mg/kg, no more than 0.7 mg/kg, no more than 0.73mg/kg, no more than 0.75 mg/kg, no more than 0.78 mg/kg, no more than0.8 mg/kg, no more than 0.83 mg/kg, no more than 0.85 mg/kg, no morethan 0.87 mg/kg, no more than 0.9 mg/kg, no more than 0.95 mg/kg, nomore than 1 mg/kg, no more than 1.1 mg/kg, no more than 1.2 mg/kg, nomore than 1.3 mg/kg, no more than 1.4 mg/kg, no more than 1.5 mg/kg, nomore than 1.6 mg/kg, no more than 1.7 mg/kg, no more than 1.8 mg/kg, nomore than 1.9 mg/kg, no more than 2 mg/kg, no more than 2.1 mg/kg, nomore than 2.2 mg/kg, no more than 2.3 mg/kg, no more than 2.4 mg/kg, nomore than 2.5 mg/kg, no more than 2.6 mg/kg, no more than 2.7 mg/kg, nomore than 2.8 mg/kg, no more than 2.9 mg/kg, no more than 3 mg/kg, nomore than 3.1 mg/kg, no more than 3.2 mg/kg, no more than 3.3 mg/kg, nomore than 3.4 mg/kg, no more than 3.5 mg/kg, no more than 3.6 mg/kg, nomore than 3.7 mg/kg, no more than 3.8 mg/kg, no more than 3.9 mg/kg, nomore than 4 mg/kg, no more than 4.1 mg/kg, no more than 4.2 mg/kg, nomore than 4.3 mg/kg, no more than 4.4 mg/kg, no more than 4.5 mg/kg, nomore than 4.6 mg/kg, no more than 4.7 mg/kg, no more than 4.8 mg/kg, nomore than 4.9 mg/kg, no more than 5 mg/kg, no more than 6 mg/kg, no morethan 7 mg/kg, no more than 8 mg/kg, no more than 9 mg/kg, or no morethan 10 mg/kg.

In some embodiments, the amount of 5HT receptor agonist, orpharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the pharmaceutical composition corresponds to about1% w/w to about 50% w/w of the solids in the oral liquid formulation. Inother embodiments, the amount of the pharmaceutically acceptable salt ofa 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof correspond to about 1% w/w,about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9%w/w, about 2% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8%w/w, about 2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7%w/w, about 3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6%w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5% w/w, about5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about 5.5%w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w,about 6% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4%w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w,about 6.9% w/w, about 7% w/w, about 7.1% w/w, about 7.2% w/w, about 7.3%w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w, about 7.7% w/w,about 7.8% w/w, about 7.9% w/w, about 8% w/w, about 8.1% w/w, about 8.2%w/w, about 8.3% w/w, about 8.4% w/w, about 8.5% w/w, about 8.6% w/w,about 8.7% w/w, about 8.8% w/w, about 8.9% w/w, about 9% w/w, about 9.1%w/w, about 9.2% w/w, about 9.3% w/w, about 9.4% w/w, about 9.5% w/w,about 9.6% w/w, about 9.7% w/w, about 9.8% w/w, about 9.9% w/w, about10% w/w, about 10.2% w/w, about 10.4% w/w, about 10.6% w/w, about 10.8%w/w, about 11% w/w, about 11.2% w/w, about 11.4% w/w, about 11.6% w/w,about 11.8% w/w, about 12% w/w, about 12.2% w/w, about 12.4% w/w, about12.6% w/w, about 12.8% w/w, about 13% w/w, about 13.2% w/w, about 13.4%w/w, about 13.6% w/w, about 13.8% w/w, about 14% w/w, about 14.2% w/w,about 14.4% w/w, about 14.6% w/w, about 14.8% w/w, about 15% w/w, about15.5% w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5%w/w, about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w,about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24%w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about29% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about 33% w/w,about 34% w/w, about 35% w/w, about 36% w/w, about 37% w/w, about 38%w/w, about 39% w/w, about 40% w/w, about 41% w/w, about 42% w/w, about43% w/w, about 44% w/w, about 45% w/w, about 46% w/w, about 47% w/w,about 48% w/w, about 49% w/w, or about 50% w/w of the solids in the oralliquid formulation.

Therapeutic Uses—Disorders, Conditions and Symptoms

Provided herein are methods for managing disorders or conditions,comprising administering one or more 5HT receptor agonists, orpharmaceutically acceptable salts, solvates, metabolites, derivatives,or prodrugs thereof.

Further provided herein are methods of treating symptoms of disorders orconditions, comprising administering one or more 5HT receptor agonists,or pharmaceutically acceptable salts, solvates, metabolites,derivatives, or prodrugs thereof.

In some embodiments, the disorders or conditions are neurologicaldisorders or conditions. In some embodiments, the disorders orconditions are neurocognitive disorders or conditions. In someembodiments, the disorders or conditions are neurodegenerative disordersor conditions. In some embodiments, the symptoms of the neurologicalcondition are physical, behavioral, emotional, mental, or a combinationthereof.

Provided herein are methods for managing or treating disorders,conditions or symptoms including but not limited to addiction disorders,such as but not limited to alcohol abuse, substance abuse, smoking, orobesity. Provided herein are methods for managing or treating disorders,conditions or symptoms including but not limited to eating disorders andauditory disorders. Provided herein are methods for managing or treatingdisorders, conditions or symptoms including but not limited to pain,such as but not limited to chronic pain. Provided herein are methods formanaging or treating disorders, conditions or symptoms including but notlimited to depression, bipolar disorder, post-traumatic stress disorder(PTSD), panic disorder, phobia, schizophrenia, psychopathy, orantisocial personality disorder. Provided herein are methods formanaging or treating disorders, conditions or symptoms including but notlimited to impulse disorders, such as but not limited to attentiondeficit hyperactivity disorder (ADHD), Tourette's syndrome or autism.Provided herein are methods for managing or treating disorders,conditions or symptoms including but not limited to compulsive disorder,such as but not limited to obsessive compulsive disorder (OCD),gambling, or aberrant sexual behavior. Provided herein are methods formanaging or treating disorders, conditions or symptoms including but notlimited to personality disorders, such as but not limited to conductdisorder, antisocial personality, or aggressive behavior.

Further examples of the disorders, conditions and symptoms which may bemanaged or treated include, by way of non-limiting examples:

Neurodevelopmental disorders such as, but not limited to,attention-deficit/hyperactivity disorder (ADHD), autism spectrumdisorder, learning disorders and the like.

Schizophrenia spectrum and other psychotic disorders including but notlimited to detachment from reality, delusions, hallucinations, anddisorganized thinking and speech.

Bipolar and related disorders which may involve episodes of mania(periods of excessive excitement, activity, and energy) alternating withperiods of depression.

Depressive disorders which may involve feelings of extreme sadness,reduced interest in previously enjoyable activities, including but notlimited to depression, severe depression, major depressive disorder(MDD), premenstrual dysphoric disorder (PMDD) and the like.

Anxiety disorders which may involve worrying excessively about potentialbad things or situations. Examples include generalized anxiety disorder(GAD), panic disorder and phobias (irrational fears of specific things)and the like.

Obsessive-compulsive and related disorders which may involve repeated,unwanted urges, thoughts, or images (obsessions) and feeling driven totaking repeated actions in response to them (compulsions). Non-limitingexamples include obsessive-compulsive disorder (OCD), hoarding disorder,extreme nail biting, and hair-pulling disorder (trichotillomania).

Trauma and stressor-related disorders which may develop during or afterstressful or traumatic life events. Non-limiting examples includepost-traumatic stress disorder (PTSD) and acute stress disorder.

Dissociative disorders wherein the sense of self is may be disrupted,such as but not limited to dissociative identity disorder, dissociativeamnesia and the like.

Somatic symptom and related disorders which may involve distressing andincapacitating physical symptoms with no clear medical cause.Non-limiting examples include illness anxiety disorder, somatic symptomdisorder (hypochondriasis), factitious disorder and the like.

Feeding and eating disorders which may involve disturbances related toeating, such as but not limited to anorexia nervosa, bulimia nervosa,and binge eating disorder.

Elimination disorders which may involve inappropriate elimination(release) of urine or stool by accident or deliberately, such as but notlimited to bedwetting (enuresis).

Sleep-wake disorders which may involve severe sleep disorders, includingbut not limited to insomnia disorder, nightmare disorder, sleep apnea,and restless legs syndrome.

Disruptive, impulse-control, and conduct disorders which may involvedifficulty with emotional and/or behavioral self-control, such as butnot limited to kleptomania (repeated stealing), pyromania, andintermittent explosive disorder.

Substance-related disorders which may involve problems associated withexcessive use of substances such as alcohol (alcohol dependence,alcoholism), tobacco products, drugs, opioids (for example, cocaine,oxycodone, morphine and the like), recreational drugs, hallucinogens andthe like.

Addictive disorders which may involve problems associated with excessiveuse of particular behaviors or fixations, such as but not limited togambling disorder.

Neurocognitive disorders which may affect the ability to think andreason, such as but not limited to traumatic brain injury (TBI),Alzheimer's disease and the like.

Personality disorders which may involve enduring patterns of emotionalinstability and unhealthy behaviors that disrupt daily living andrelationships. Examples include but are not limited to borderline,antisocial, and narcissistic personality disorders.

Gender dysphoria which may involve distress caused by a person's desireto be a different gender.

Sexual dysfunctions such as but not limited to premature ejaculation,erectile disorder, and female orgasmic disorder.

Paraphilic disorders (sexual perversion, sexual deviation) which mayinvolve sexual interest in atypical objects, situations, fantasies,behaviors, or individuals. Examples include but are not limited tosexual sadism disorder, voyeuristic disorder, and pedophilic disorder.

Further examples of the disorders, conditions and symptoms which may bemanaged or treated include by way of non-limiting example, Fragile Xsyndrome, Down syndrome, migraine headache, cluster headache,psychiatric disorders, neurodevelopmental disorders,attention-deficit/hyperactivity disorder (ADHD), autism spectrumdisorder, learning disorders, schizophrenia spectrum, psychoticdisorders, bipolar disorders, depression, severe depression, majordepressive disorder (MDD), premenstrual dysphoric disorder (PMDD),suicidality, mood related disorders, panic disorder, panic attack,phobias, agoraphobia, selective mutism, obsessive-compulsive disorder(OCD), hoarding disorder, hair-pulling disorder (trichotillomania),excoriation (skin-picking) disorder, substance-/medication-inducedobsessive-compulsive disorder, trauma-related disorders, traumatic braininjury (TBI), post-traumatic stress disorder (PTSD), acute stressdisorder, dissociative disorders, dissociative identity disorder,dissociative amnesia, anxiety, anxiety disorders, generalized anxietydisorder (GAD), social anxiety disorder, separation anxiety disorder,illness anxiety disorders, somatic disorders and diseases, somaticsymptom disorder (hypochondriasis), factitious disorder, feedingdisorders, eating disorders, anorexia, anorexia nervosa, bulimianervosa, binge eating disorder, elimination disorders, enuresis, sleepdisorders, insomnia, nightmare disorder, sleep apnea, central sleepapnea, narcolepsy, obstructive sleep apnea, hypopnea, and sleep-relatedhypoventilation, restless legs syndrome, jet lag, sexual dysfunction,premature ejaculation, erectile disorder, female orgasmic disorder,gender identity disorder, gender dysphoria, disruptive disorders,impulse-control disorders, conduct disorders, disruptive conductdisorders, impulse-control disorders, oppositional defiant disorder(ODD), aggression, kleptomania, pyromania, addictive disorders,substance dependence, substance abuse, alcoholism, drug addiction,opioid addiction, cocaine addiction, gambling addiction, tobaccodependence, food addiction, other forms of addiction to substances andbehaviors, obesity, cognitive disorders, memory related disorders,learning related disorders, neurocognitive disorders, Alzheimer'sdisease, personality disorders, narcissistic personality disorders,Asperger syndrome, Tourette syndrome, Huntington's disease, Parkinson'sdisease, Lewy body disease, amyotrophic lateral sclerosis (ALS),Friedreich's ataxia, muscular atrophy, prion disease, dementia, vasculardementia, dementia/neurocognitive issues due to infection, dementia dueto substance abuse or exposure to toxins, frontotemporal degeneration,mood disorders, delirium, aphasia, apraxia, agnosia, concussion,amnesia, anterograde amnesia, retrograde amnesia, body dysmorphicdisorder, reactive attachment disorder, Fragile X syndrome, Downsyndrome, migraines, migraine headache, cluster headache, cardiovasculardisease, inflammatory conditions, fibromyalgia and pain.

Provided herein are methods for managing disorders or conditions, ortreating symptoms of disorders or conditions, comprising administeringone or more 5HT receptor agonists, or pharmaceutically acceptable salts,solvates, metabolites, derivatives, or prodrugs thereof. In someembodiments, the 5HT receptor agonist is a 5HT2 receptor agonist. Insome embodiments, the 5HT2 receptor agonist is a 5HT_(2A) receptoragonist, a 5HT2B receptor agonist and/or a 5HT2C receptor agonist. Insome embodiments, the 5HT receptor agonist is psilocin or psilocybin ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof. In some embodiments, the therapeutically effectiveamount of the 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof is provided tothe subject in need thereof in an amount insufficient to provide anadverse side effect, such as hallucinogenic experience.

In some embodiments, the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of 6 ng/mL or more. In someembodiments, the therapeutically effective amount of 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof is provided to a subject in need thereofin an amount and/or formulation to provide a maximum plasmaconcentration (C_(max)) of (e.g. active form of the) 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof of about 0.1 ng/mL or more and less than6 ng/mL (e.g. at least 0.5 ng/mL and less than 6 ng/mL, about 1 ng/mL toabout 5.5 ng/mL, about 2 ng/mL to about 5 ng/mL, or the like). In someembodiments, the therapeutically effective amount of 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof is provided to a subject in need thereofin an amount and/or formulation to provide a plasma concentration of(e.g. active form of the) 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ofat least 0.1 ng/mL (e.g. at least 0.2 ng/mL, at least 0.3 ng/mL, atleast 0.5 ng/mL, or the like) after at least 6 hours (e.g. at least 12hours, at least 24 hours, at least 36 hours, at least 48 hours, at least72 hours, at least 96 hours, at least 120 hours, at least 144 hours, orthe like).

In some embodiments, the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of about 0.001 ng/mL to about10 ng/mL. In some embodiments, the therapeutically effective amount of5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of about 0.01 ng/mL to about5 ng/mL. In some embodiments, the therapeutically effective amount of5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of about 0.05 ng/mL to about1 ng/mL. In other embodiments, the therapeutically effective amount of5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of about 0.001 ng/mL, about0.005 ng/mL, about 0.01 ng/mL, about 0.02 ng/mL, about 0.03 ng/mL, about0.04 ng/mL, about 0.05 ng/mL, about 0.06 ng/mL, about 0.07 ng/mL, about0.08 ng/mL, about 0.09 ng/mL, about 0.1 ng/mL, about 0.11 ng/mL, about0.12 ng/mL, about 0.15 ng/mL, about 0.17 ng/mL, about 0.2 ng/mL, about0.23 ng/mL, about 0.25 ng/mL, about 0.28 ng/mL, about 0.3 ng/mL, about0.33 ng/mL, about 0.35 ng/mL, about 0.37 ng/mL, about 0.4 ng/mL, about0.43 ng/mL, about 0.45 ng/mL, about 0.47 ng/mL, about 0.5 ng/mL, about0.53 ng/mL, about 0.55 ng/mL, about 0.57 ng/mL, about 0.6 ng/mL, about0.63 ng/mL, about 0.65 ng/mL, about 0.67 ng/mL, about 0.7 ng/mL, about0.73 ng/mL, about 0.75 ng/mL, about 0.78 ng/mL, about 0.8 ng/mL, about0.83 ng/mL, about 0.85 ng/mL, about 0.87 ng/mL, about 0.9 ng/mL, about0.95 ng/mL, about 1 ng/mL, about 1.1 ng/mL, about 1.2 ng/mL, about 1.3ng/mL, about 1.4 ng/mL, about 1.5 ng/mL, about 1.6 ng/mL, about 1.7ng/mL, about 1.8 ng/mL, about 1.9 ng/mL, about 2 ng/mL, about 2.1 ng/mL,about 2.2 ng/mL, about 2.3 ng/mL, about 2.4 ng/mL, about 2.5 ng/mL,about 2.6 ng/mL, about 2.7 ng/mL, about 2.8 ng/mL, about 2.9 ng/mL,about 3 ng/mL, about 3.1 ng/mL, about 3.2 ng/mL, about 3.3 ng/mL, about3.4 ng/mL, about 3.5 ng/mL, about 3.6 ng/mL, about 3.7 ng/mL, about 3.8ng/mL, about 3.9 ng/mL, about 4 ng/mL, about 4.1 ng/mL, about 4.2 ng/mL,about 4.3 ng/mL, about 4.4 ng/mL, about 4.5 ng/mL, about 4.6 ng/mL,about 4.7 ng/mL, about 4.8 ng/mL, about 4.9 ng/mL, about 5 ng/mL, about5.1 ng/mL, about 5.2 ng/mL, about 5.3 ng/mL, about 5.4 ng/mL, about 5.5ng/mL, about 5.6 ng/mL, about 5.7 ng/mL, about 5.8 ng/mL, about 5.9ng/mL, or about 6 ng/mL.

In other embodiments, the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of no less than 0.001 ng/mL,no less than 0.005 ng/mL, no less than 0.01 ng/mL, no less than 0.02ng/mL, no less than 0.03 ng/mL, no less than 0.04 ng/mL, no less than0.05 ng/mL, no less than 0.06 ng/mL, no less than 0.07 ng/mL, no lessthan 0.08 ng/mL, no less than 0.09 ng/mL, no less than 0.1 ng/mL, noless than 0.11 ng/mL, no less than 0.12 ng/mL, no less than 0.15 ng/mL,no less than 0.17 ng/mL, no less than 0.2 ng/mL, no less than 0.23ng/mL, no less than 0.25 ng/mL, no less than 0.28 ng/mL, no less than0.3 ng/mL, no less than 0.33 ng/mL, no less than 0.35 ng/mL, no lessthan 0.37 ng/mL, no less than 0.4 ng/mL, no less than 0.43 ng/mL, noless than 0.45 ng/mL, no less than 0.47 ng/mL, no less than 0.5 ng/mL,no less than 0.53 ng/mL, no less than 0.55 ng/mL, no less than 0.57ng/mL, no less than 0.6 ng/mL, no less than 0.63 ng/mL, no less than0.65 ng/mL, no less than 0.67 ng/mL, no less than 0.7 ng/mL, no lessthan 0.73 ng/mL, no less than 0.75 ng/mL, no less than 0.78 ng/mL, noless than 0.8 ng/mL, no less than 0.83 ng/mL, no less than 0.85 ng/mL,no less than 0.87 ng/mL, no less than 0.9 ng/mL, no less than 0.95ng/mL, no less than 1 ng/mL, no less than 1.1 ng/mL, no less than 1.2ng/mL, no less than 1.3 ng/mL, no less than 1.4 ng/mL, no less than 1.5ng/mL, no less than 1.6 ng/mL, no less than 1.7 ng/mL, no less than 1.8ng/mL, no less than 1.9 ng/mL, no less than 2 ng/mL, no less than 2.1ng/mL, no less than 2.2 ng/mL, no less than 2.3 ng/mL, no less than 2.4ng/mL, no less than 2.5 ng/mL, no less than 2.6 ng/mL, no less than 2.7ng/mL, no less than 2.8 ng/mL, no less than 2.9 ng/mL, no less than 3ng/mL, no less than 3.1 ng/mL, no less than 3.2 ng/mL, no less than 3.3ng/mL, no less than 3.4 ng/mL, no less than 3.5 ng/mL, no less than 3.6ng/mL, no less than 3.7 ng/mL, no less than 3.8 ng/mL, no less than 3.9ng/mL, no less than 4 ng/mL, no less than 4.1 ng/mL, no less than 4.2ng/mL, no less than 4.3 ng/mL, no less than 4.4 ng/mL, no less than 4.5ng/mL, no less than 4.6 ng/mL, no less than 4.7 ng/mL, no less than 4.8ng/mL, no less than 4.9 ng/mL, no less than 5 ng/mL, no less than 5.1ng/mL, no less than 5.2 ng/mL, no less than 5.3 ng/mL, no less than 5.4ng/mL, no less than 5.5 ng/mL, no less than 5.6 ng/mL, no less than 5.7ng/mL, no less than 5.8 ng/mL, or no less than 5.9 ng/mL.

In other embodiments, the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation insufficient to provide amaximum plasma concentration (C_(max)) of (e.g. active form of the) 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof of no more than 0.005 ng/mL,no more than 0.01 ng/mL, no more than 0.02 ng/mL, no more than 0.03ng/mL, no more than 0.04 ng/mL, no more than 0.05 ng/mL, no more than0.06 ng/mL, no more than 0.07 ng/mL, no more than 0.08 ng/mL, no morethan 0.09 ng/mL, no more than 0.1 ng/mL, no more than 0.11 ng/mL, nomore than 0.12 ng/mL, no more than 0.15 ng/mL, no more than 0.17 ng/mL,no more than 0.2 ng/mL, no more than 0.23 ng/mL, no more than 0.25ng/mL, no more than 0.28 ng/mL, no more than 0.3 ng/mL, no more than0.33 ng/mL, no more than 0.35 ng/mL, no more than 0.37 ng/mL, no morethan 0.4 ng/mL, no more than 0.43 ng/mL, no more than 0.45 ng/mL, nomore than 0.47 ng/mL, no more than 0.5 ng/mL, no more than 0.53 ng/mL,no more than 0.55 ng/mL, no more than 0.57 ng/mL, no more than 0.6ng/mL, no more than 0.63 ng/mL, no more than 0.65 ng/mL, no more than0.67 ng/mL, no more than 0.7 ng/mL, no more than 0.73 ng/mL, no morethan 0.75 ng/mL, no more than 0.78 ng/mL, no more than 0.8 ng/mL, nomore than 0.83 ng/mL, no more than 0.85 ng/mL, no more than 0.87 ng/mL,no more than 0.9 ng/mL, no more than 0.95 ng/mL, no more than 1 ng/mL,no more than 1.1 ng/mL, no more than 1.2 ng/mL, no more than 1.3 ng/mL,no more than 1.4 ng/mL, no more than 1.5 ng/mL, no more than 1.6 ng/mL,no more than 1.7 ng/mL, no more than 1.8 ng/mL, no more than 1.9 ng/mL,no more than 2 ng/mL, no more than 2.1 ng/mL, no more than 2.2 ng/mL, nomore than 2.3 ng/mL, no more than 2.4 ng/mL, no more than 2.5 ng/mL, nomore than 2.6 ng/mL, no more than 2.7 ng/mL, no more than 2.8 ng/mL, nomore than 2.9 ng/mL, no more than 3 ng/mL, no more than 3.1 ng/mL, nomore than 3.2 ng/mL, no more than 3.3 ng/mL, no more than 3.4 ng/mL, nomore than 3.5 ng/mL, no more than 3.6 ng/mL, no more than 3.7 ng/mL, nomore than 3.8 ng/mL, no more than 3.9 ng/mL, no more than 4 ng/mL, nomore than 4.1 ng/mL, no more than 4.2 ng/mL, no more than 4.3 ng/mL, nomore than 4.4 ng/mL, no more than 4.5 ng/mL, no more than 4.6 ng/mL, nomore than 4.7 ng/mL, no more than 4.8 ng/mL, no more than 4.9 ng/mL, nomore than 5 ng/mL, no more than 5.1 ng/mL, no more than 5.2 ng/mL, nomore than 5.3 ng/mL, no more than 5.4 ng/mL, no more than 5.5 ng/mL, nomore than 5.6 ng/mL, no more than 5.7 ng/mL, no more than 5.8 ng/mL, nomore than 5.9 ng/mL, or no more than 6 ng/mL.

In some embodiments, the pharmaceutical composition is an oralformulation, a buccal formulation, a nasal formulation, or an inhalationformulation. In some embodiments, the pharmaceutical composition is in aform selected from a spray, aerosol, mist, nebulae, ointment, cream,gel, paste, salve, solution, suspension, tincture, patch, and atomizedvapor.

Therapeutic Regimens

In some embodiments, any pharmaceutical composition or formulation or5HT receptor agonist agent disclosed herein is administered fortherapeutic application. In some embodiments, the pharmaceuticalcomposition or formation or 5HT receptor agonist agent is administeredonce per day, twice per day, three times per day or more. In certainembodiments, the pharmaceutical composition or formulation or 5HTreceptor agonist agent is administered daily, every day, every alternateday, five days a week, once a week, every other week, two weeks permonth, three weeks per month, once a month, twice a month, three timesper month, or more. In some embodiments, the pharmaceutical compositionor formulation or 5HT receptor agonist agent is administered for atleast 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months,2 years, 3 years, or more.

In some embodiments, one or more pharmaceutical compositions areadministered simultaneously, sequentially, or at an interval period oftime. In some embodiments, one or more pharmaceutical compositions areadministered simultaneously. In some cases, one or more pharmaceuticalcompositions are administered sequentially. In additional cases, one ormore pharmaceutical compositions are administered at an interval periodof time (e.g. the first administration of a first pharmaceuticalcomposition is on day one followed by an interval of at least 1, 2, 3,4, 5, or more days prior to the administration of at least a secondpharmaceutical composition).

In some embodiments, two or more different pharmaceutical compositionsare co-administered. In some instances, the two or more differentpharmaceutical compositions are co-administered simultaneously. In somecases, the two or more different pharmaceutical compositions areco-administered sequentially without a gap of time betweenadministrations. In other cases, the two or more differentpharmaceutical compositions are co-administered sequentially with a gapof about 0.5 hour, 1 hour, 2 hour, 3 hour, 12 hours, 1 day, 2 days, ormore between administrations.

In some embodiments, the amount of a given agent that corresponds tosuch an amount varies depending upon factors such as the particularcompound, the severity of the disease, the identity (e.g. weight) of thesubject or host in need of treatment, but nevertheless is routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g. the specific agentbeing administered, the route of administration, and the subject or hostbeing treated. In some instances, the desired dose is convenientlypresented in a single dose or as divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesis altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Kits/Article of Manufacture

Provided herein, in certain embodiments, are kits and articles ofmanufacture for use with one or more of the pharmaceutical compositions,formulations, and/or dosage forms of 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof disclosed herein. Such kits include a carrier, package,or container that is compartmentalized to receive one or more containerssuch as vials, tubes, and the like, each of the container(s) comprisingone of the separate elements to be used in a method disclosed herein.Suitable containers include, for example, bottles, vials, syringes, andtest tubes. In one embodiment, the containers are formed from a varietyof materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, bags, containers, bottles,and any packaging material suitable for a selected formulation andintended mode of administration and treatment.

For example, the container(s) include a composition of 5HT receptoragonist, or pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof disclosed herein. Such kits optionallyinclude an identifying description or label or instructions relating toits use in the methods disclosed herein.

A kit typically includes labels listing contents and/or instructions foruse, and package inserts with instructions for use. A set ofinstructions will also typically be included.

In one embodiment, a label is on or associated with the container. Inone embodiment, a label is on a container when letters, numbers or othercharacters forming the label are attached, molded or etched into thecontainer itself; a label is associated with a container when it ispresent within a receptacle or carrier that also holds the container,e.g. as a package insert. In one embodiment, a label is used to indicatethat the contents are to be used for a specific therapeutic application.The label also indicates directions for use of the contents, such as inthe methods disclosed herein.

In certain embodiments, the pharmaceutical compositions are presented ina pack or dispenser device which contains one or more unit dosage formscomprising a 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof. The pack, forexample, contains metal or plastic foil, such as a blister pack. In someembodiments, the pack contains the pharmaceutical compositions describedherein and a second agent. In certain embodiments, the pharmaceuticalcompositions are presented in a pack or dispenser device which containsone or more unit dosage forms comprising a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof, and one or more unit dosage forms comprising a secondagent. In some embodiments, the second agent is a placebo. In someembodiments, the second agent is a therapeutic agent. In someembodiments, the pack is organized to aid patient compliance as to whichagent to take at which time and/or on which day. In some embodiments,the pack or dispenser device is accompanied by instructions foradministration. In one embodiment, the pack or dispenser is alsoaccompanied with a notice associated with the container in formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the drug for human or veterinary administration.Such notice, for example, is the labeling approved by the U.S. Food andDrug Administration for prescription drugs, or the approved productinsert. In one embodiment, compositions comprising a 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof formulated in a compatible pharmaceuticalcarrier are also prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. It is to be understoodthat the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof any subject matter claimed. In this application, the use of thesingular includes the plural unless specifically stated otherwise. Itmust be noted that, as used in the specification and the appendedclaims, the singular forms “a”, “an”, and “the” include plural referentsunless the context clearly dictates otherwise. In this application, theuse of “or” means “and/or” unless stated otherwise. Furthermore, use ofthe term “including” as well as other forms, such as “include”,“includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter disclosed.

As used herein, the terms “individual(s)”, “subject(s)” and “patient(s)”mean any mammal. In some embodiments, the mammal is a human. In someembodiments, the mammal is a non-human. None of the terms require or arelimited to situations characterized by the supervision (e.g. constant orintermittent) of a health care worker (e.g. a doctor, a registerednurse, a nurse practitioner, a physician's assistant, an orderly or ahospice worker).

As used herein, ranges and amounts can be expressed as “about” aparticular value or range. About also includes the exact amount. Hence“about 5 μL” means “about 5 μL” and also “5 μL.” Generally, the term“about” includes an amount that would be expected to be withinexperimental error.

The terms “controlled release dosage form” and “controlled releaselayer” are used interchangeably and defined as those whose drug releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventionalimmediate release dosage forms. The rate of release of the active drugfrom a controlled release layer or dosage form is controlled by featuresof the dosage form and/or in combination with physiologic orenvironmental conditions rather than by physiologic or environmentalconditions alone. The controlled release dosage forms are used tomaintain drug plasma levels within the therapeutic window. Thecontrolled release dosage forms of certain embodiments attempt todeliver therapeutically effective amounts of active drug as a once-dailydose so that the ratio C_(max)/C_(min) in the plasma at steady state isless than the therapeutic index, and to maintain drug levels at constanteffective levels to provide a therapeutic benefit over a period of time(e.g. 24-hour period). In certain embodiments controlled release dosageforms provide a substantially constant or gradually decreasing rate ofdrug release so as to provide plasma levels which remain substantiallyinvariant with time. In certain embodiments controlled release dosageforms are designed to provide a quick increase in the plasmaconcentration of the drug which remains substantially constant withinthe therapeutic range of the drug for a period of time (e.g. 24-hourperiod). Alternatively, in some other embodiments controlled releasedosage forms are designed to provide a quick increase in the plasmaconcentration of the drug, which although might not remain constant,declines at a rate such that the plasma concentration remains within thetherapeutic range for a period of time (e.g. 24-hour period).

The term “controlled release matrix” refers to a polymeric matrix thatis capable of delivering a bioactive agent at a controlled rate for aperiod of time. Although there might be an initial burst phase, theoverall release kinetics of the bioactive agent from the matrix aregenerally linear, such that a relatively constant supply of bioactiveagent is released over the desired time period. The time period mightvary from several hours to several days, depending upon the bioactiveagent and its intended use. In general, it is preferable that thepercentage of bioactive agent released from the controlled matrix overthe treatment period be relatively high (e.g. at least about 50%, atleast about 75%, at least about 90%, or at least about 95%) to avoidwaste of unreleased bioactive agent.

The term “immediate release” layer or dosage form refers to the releaseof an active agent substantially immediately upon administration. Forexample, immediate release includes but not limited to contact withgastric juices and results in substantially complete dissolution withinabout 1 hour. Immediate release components might also be referred to asinstant release. When used in association with the dissolution profilesdiscussed herein, the term “immediate release” refers to that portion ofa dosage form disclosed herein which delivers active agent over a periodof time less than 1 hour.

The terms “coating composition”, “coat composition”, “coating solution”,“coat solution”, “coating suspension”, and “coat suspension” as usedherein are used interchangeably and are defined to mean a mixture ofexcipients that is used to create a controlled release coating. Thecoating composition is applied onto a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof core to form an intermediate coating, and theintermediate coating is cured to form the controlled release coating.

The terms “effective amount” or “pharmaceutically effective amount” or“therapeutically effective amount” refer to a nontoxic but sufficientamount of the agent to provide the desired biological, therapeutic,and/or prophylactic result. That result might be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of a 5HT receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof as disclosed herein per se or a composition comprising a5HT receptor agonist or a pharmaceutically acceptable salt, solvate;metabolite, derivative, or prodrug thereof as disclosed herein requiredto provide a clinically significant decrease in a disease. Anappropriate effective amount in any individual case might be determinedby one of ordinary skill in the art using routine experimentation.

In some instances, the term “low dose” as used herein refers to anamount of a therapeutic agent (e.g. a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof), which is sufficient to provide the desired biological,therapeutic, and/or prophylactic result, while insufficient to induce anundesired effect (e.g. such as a hallucinogenic experience, aperturbation in the user's sense of reality or perceptions).

The term “mucoadhesive agent” refers to an agent that adheres to amucous membrane. The mucous membrane consists of one or more layers ofepithelial cells overlying a layer of loose connective tissue. Examplesof mucous membranes include, but not limited to, tongue mucosa,bronchial mucosa, endometrium, esophageal mucosa, gastric mucosa,intestinal mucosa, nasal mucosa, olfactory mucosa, oral mucosa, penilemucosa, vaginal mucosa, and anal mucosa.

The term “transmucosal administration” refers to the route ofadministration in which the drug is diffused through the mucousmembrane. This might refer to inhalation, nasal, sublingual, vaginal,rectal, or ocular routes.

The term “5HT receptor agonist agent” refers to a 5HT receptor agonistas a free base or a derivative or analog thereof. Included in the termare salts, solvates, metabolites, prodrugs, isomers, tautomers, isotopicderivatives, and the like, of a 5HT receptor agonist. In someembodiments, the derivative, analogs, salts, solvates, metabolites,prodrugs, isomers, tautomers, isotopic derivatives, etc. arepharmaceutically acceptable derivative, analogs, salts, solvates,metabolites, prodrugs, isomers, tautomers, isotopic derivatives of a 5HTreceptor agonist.

The term “pharmaceutically acceptable,” as used herein, refers amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynontoxic, i.e., the material is administered to an individual withoutcausing undesirable biological effects or interacting in a deleteriousmanner with any of the components of the composition in which it iscontained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation (Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties Selection and Use,Weinheim/Zürich:Wiley-VCH/VHCA, 2002). Pharmaceutical salts typicallyare more soluble and more rapidly soluble in stomach and intestinaljuices than non-ionic species and so are useful in solid dosage forms.Furthermore, because their solubility often is a function of pH,selective dissolution in one or another part of the digestive tract ispossible and this capability can be manipulated as one aspect of delayedand sustained release behaviors. Also, because the salt-forming moleculecan be in equilibrium with a neutral form, passage through biologicalmembranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with an acid to provide a“pharmaceutically acceptable acid addition salt,” 0.1n some embodiments,the compound described herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,metaphosphoric acid, nitric acid, phosphoric acid, and sulfuric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesuifonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethylfumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid;nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid;proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacic acid;stearic acid; succinic acid; sulfuric acid; tartaric acid (+L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound described herein is prepared as achloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt,citrate salt or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound described herein with a base to provide a“pharmaceutically acceptable base addition salt”. In some embodiments,the compound described herein is acidic and is reacted with a base. Insuch situations, an acidic proton of the compound described herein isreplaced by a metal ion, e.g. lithium, sodium, potassium, magnesium,calcium, or an aluminum ion. In some cases, compounds described hereincoordinate with an organic base, such as, but not limited to,ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms, i.e. solvates. Insome embodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of isolating or purifying the compound with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein areconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein optionally exist inunsolvated as well as solvated forms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds described herein, aswell as active metabolites of these compounds having the same type ofactivity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds described herein are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements. In some embodiments, one or more hydrogen atoms of thecompounds described herein is replaced with deuterium.

In some embodiments, the compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, atropisomers, and epimeric forms as wellas the appropriate mixtures thereof. The compounds and methods providedherein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns. In certain embodiments, compoundsdescribed herein are prepared as their individual stereoisomers byreacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds/salts,separating the diastereomers and recovering the optically pureenantiomers. In some embodiments, resolution of enantiomers is carriedout using covalent diastereomeric derivatives of the compounds describedherein. In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of stereoisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof (JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981). In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. The prodrug might be a substrate for a transporter.Further or alternatively, the prodrug also has improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) but then ismetabolically hydrolyzed to provide the active entity. A further exampleof a prodrug is a short peptide (polyamino acid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety. In certainembodiments, upon in vivo administration, a prodrug is chemicallyconverted to the biologically, pharmaceutically or therapeuticallyactive form of the compound. In certain embodiments, a prodrug isenzymatically metabolized by one or more steps or processes to thebiologically, pharmaceutically or therapeutically active form of thecompound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference. In some embodiments, ahydroxyl group in the compounds disclosed herein is used to form aprodrug, wherein the hydroxyl group is incorporated into an acyloxyalkylester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphateester, sugar ester, ether, and the like. In some embodiments, a hydroxylgroup in the compounds disclosed herein is a prodrug wherein thehydroxyl is then metabolized in vivo to provide a carboxylic acid group.In some embodiments, a carboxyl group is used to provide an ester oramide (i.e. the prodrug), which is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, compounds described hereinare prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound described herein as set forthherein are included within the scope of the claims. In some cases, someof the herein-described compounds is a prodrug for another derivative oractive compound.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes might produce specific structural alterations toa compound. For example, cytochrome P450 catalyzes a variety ofoxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Metabolites of thecompounds disclosed herein are optionally identified either byadministration of compounds to a host and analysis of tissue samplesfrom the host, or by incubation of compounds with hepatic cells in vitroand analysis of the resulting compounds.

A compound is “dissolved” when it is “in solution”, and does notspontaneously come out of solution to from a separate phase. In order tobe dissolved, the compound need not dissociate completely on a molecularlevel, but must remain in solution so as to be effective in treatment ofa disease or condition. A dissolved compound might be present in amicellar, emulsified, or liposomal form.

“Solubility” generally means the amount of a compound dissolved in asolvent. Suitable solvents include aqueous and non-aqueous solvents.

“Poor solubility” means a small amount of compound dissolved in asolvent. Poor solubility is not an absolute term, but depends on theamount of the compound that is needed for effective treatment of adisease or condition. A compound will be poorly soluble if itssolubility is lower than is desired in order for an effective treatmentof a disease or condition.

“Enhanced solubility” means higher solubility than for a 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof alone. Enhanced solubility in water canbe useful because many bodily fluids such as blood are water based(aqueous) and therefore, a more water soluble drug might have higherbioavailability. While the exact solubility of a compound in pure wateris not the same as in an aqueous solution such as blood, a composition'ssolubility in pure water is often a good indication of solubility inother aqueous solutions.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mightexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

The term “taste masking agents” when used herein refers to tastereceptor blockers, compounds which mask the chalkiness, grittiness,dryness and/or astringent taste properties of an active compound,compounds which reduce throat catch as well as compounds which add aflavor.

The term “enhancers” when used herein refers to agents which work toincrease membrane permeability and/or work to increase the solubility ofa particular active. Both issues can be pivotal to the properties of theformulation. The following are examples. Chelators: EDTA, citric acid,sodium salicylate, methoxysalicylates (see Senel & Hincal: JCR 72 2001133-144; Malhalingam et al.: AAPS Pharmascitech 2007 (8) vol 3 Article55). Surfactants: sodium lauryl sulphate, polyoxyethylene,POE-9-laurylether, POE-20-cetylether, benzalkonium chloride, 23-laurylether, cetylpyridinium chloride, cetyltrimethyl ammonium bromide,amphoteric and cationic surfactants. Membrane disrupting compounds suchas powdered alcohols (e.g. menthol and ethanol), and compounds such aslipophilic enhancers which are safe to be used orally (Nicolazzo, Reidand Finnin J Pharmaceutical Sciences Vol 93, No 8 Aug. 2004 2054-2063).Fatty and other acids: oleic acid, capric acid, lauric acid, lauricacid/propylene glycol, methyloleate, ysophosphatidylcholine,phosphatidylcholine (Sudhakar et al. JCR 114 (2006) 15-40), oleic acidco-delivered with PEG 200, (Lee and Kellaway Int J Pharmaceutics 204(2000) 137-144). Lysalbinic acid (Starokadomdkyy & Dubey Int JPharmaceutics 308 (2006) 149-154). Non-surfactants such as unsaturatedcyclic ureas. Others include: glucosaminoglycans (GAGs), aprotinin,azone, cyclodextrin, dextran sulfate, curcumin, menthol, Polysorbate 80,sulfoxides and various alkyl glycosides; Chitosan-4-thiobutylamide,chitosan-4-thiobutylamide/GSH, chitosan-cysteine, chitosan-(85% degreeN-deacetylation), poly(acrylic acid)-homocysteine,polycarbophil-cysteine, polycarbophil-cysteine/GSH,chitosan-4-thioethylamide/GSH, chitosan-4-thioglycholic acid; hyaluronicacid in 3 molecular weights (Sandri et al.: J Pharmacy and Pharmacology2004, 56: 1083-1090); bile salts (dihydroxy and trihydroxy), sodiumglycocholate, sodium deoxycholate, sodium taurocholate, sodiumglycodeoxycholate, sodium taurodeoxycholate (Artusi et al.: Int JPharmaceutics 250 (2003) 203-213); and propanolol hydrochloride (Akbariet al.: II Farmaco 59 (2004)155-161).

The term “complexing agents” when used herein includes agents in thegroup consisting of: cyclodextrins, calcium acetate, poly(methyl vinylether/maleic anhydride),

The term “treating” and its grammatical equivalents as used hereininclude achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding the fact thatthe patient might still be afflicted with the underlying disorder. Forprophylactic benefit, a method might be performed on, or a compositionmight be administered to a patient at risk of developing a disease, orto a patient reporting one or more of the physiological symptoms of suchconditions, even though a diagnosis of the condition might not have beenmade.

While generally high drug solubility is desired, is would be appreciatedby a person of ordinary skill in the art that there are otherconsiderations in creating a pharmaceutical composition such asviscosity, stability, potential toxicity, etc. that might result acomposition with lower solubility being more desirable for a particulartherapy or delivery method as long as the amount of available drug isenough for the application. Pharmaceutical compositions disclosed hereinprovide the ability to optimize these factors.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Example 1. Oral Formulation of a 5HT Receptor Agonist

A pharmaceutical composition of psilocybin is prepared as follows: 150 gof psilocybin is mixed with 30.4 g of pregelatinized starch, 23.8 g ofmicrocrystalline cellulose, 6.1 g of polyvinylpyrrolidone, and 6.1 g ofsodium starch glycollate. The mixture is blended for about 10 minutes.The resultant pharmaceutical composition is formulated into a suitabledosage form.

Example 2. Controlled Release Dosage Form

A controlled release dosage form of psilocybin 25 mg tablet is preparedas follows.

Ingredient % w/w Psilocybin HCl 90.20 Silicon dioxide 2.70 Polyvinylalcohol (PVA)* 3.00 Atomized glyceryl behenate 3.30 Magnesium stearate0.80 Total 100.00 *The PVA is prepared as a 4% solution (w/w) inpurified water. The purified water is not considered as part of thetheoretical batch size since it is evaporated during drying of the corein the fluid bed granulator.

All of the psilocybin and silicon dioxide is transferred to a V-blenderand blended for about 10 minutes. The blended material is thendischarged into a fluid bed granulator and granulation is carried out inthe presence of the PVA solution.

After drying, the granules are sized by passing the granules through a0.40 mm screen. The screened granules are then transferred to aV-blender and blended with the atomized glyceryl behenate for about 10minutes. Finally, the magnesium stearate is added and blending iscarried out for about 10 more minutes.

The psilocybin tablet cores are then coated with a controlled releasecoating formulation. The coating process is carried out in an apparatusequipped with a coating chamber. The mesh size of the bottom screen is200 μm and the size of the spray nozzle is 1 mm.

Coated tablets are dried for about 30 minutes. After application of thecoating the tablets are cured in an oven at 62±2° C. for about 2 hours.

The psilocybin tablet cores are next coated with the coating formulationto a weight gain of either 14% or 16% w/w by weight of the tablet coreand cured in an oven at from about 60° C. to about 75° C. for about 2hours to about 15 hours.

The resulted psilocybin core coated with a controlled release layer isfurther coated with an immediate-release layer comprising 15 mg ofpromethazine hydrochloride.

Example 3. Controlled Release Matrix of Psilocybin

A controlled release matrix containing psilocybin is prepared asfollows. A mixture of 25% psilocybin, or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof (such aspsilocybin HCl) is combined with a polymeric matrix such as PLGA polymerand melt extruded using a twin screw extruder (available from AmericanLEISTRITZ Extruder Corp. USA, Somerville, N.J. 08876). Psilocybin is fedin a continuous manner to the twin screw extruder from a loss-in-weightfeeder (available from K-Iron International, Inc., Pitman, N.J. 08071).The polymeric matrix is fed in a similar manner. The ratio of thebioactive agent to the polymeric matrix is controlled by the relativemass flow rate of bioactive agent from the first feeder to that of thepolymeric matrix from the second feeder. The feeders and extruder arepurged with dry air or nitrogen gas to maintain low humidity. Thepolymeric matrix is melted within the extruder operating at atemperature of 120° C. Psilocybin is not melted but is mixed within themolten and flowing polymeric matrix. The extruder forces or pumps themixed bioactive agent and polymeric matrix through a rectangular shapedorifice or die to shape the material into an extrudate with width ofabout 5 mm to about 10 mm and a thickness from about 50 μm and about 250μm. After cooling, the extrudate is cut into strips with a desiredlength and packaged. The individual strips are placed and sealed insideof a sterilization pouch such as foil-foil pouch (available from OliverProducts, 445 Sixth Street, NW, Grand Rapids, Mich. 49504 USA).

Example 4. Transmucosal Delivery of Psilocybin Compositions

Pharmaceutical composition for the nasal transmucosal deliverycontaining psilocybin, or a pharmaceutically acceptable salt, solvate,metabolite, or prodrug thereof is formulated into a suitable form, andadministered by spray as a medicine for external use.

For preparation of spray, psilocybin, or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof (such aspsilocybin HCl) is dissolved in a solvent (such as water, ethyleneglycol, or glycerin), or suspended. The concentration of psilocybin, ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof in the solution is from about 5 mg/mL, to about 50mg/mL. To the resulted solution, a mucoadhesive agent is added (such asCarbopol 974P). The concentration of the mucoadhesive agent in theresulted mixture is from about 1 mg/mL to about 25 mg/mL. The resultedmedicinal solution is filled in a container having a specific sprayingdevice (valve) with a low viscous spraying agent. For this, themedicinal solution is sprayed in the type of smog using pressure. A doseof the pharmaceutical compositions containing psilocybin, or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is 0.1 mg-10 mg/kg/day, and is altered according to thecomposition used and/or patient's condition.

Example 5. Preparation of Liposomal Psilocybin Formation

Ingredient Quantity (mg/g of cream) psilocybin 5.0 soya lecithin 200.0cholesterol 20.0 tetraglycol 100.0 dimethylisosorbide 50.0 methylparaben2.0 propylparaben 0.2 BHT 0.1 sodium chloride 1.0 HPMC 15.0 sodiumhydroxide 0.6 citric acid 1.0 purified water, USP 603.6

Heat the soya lecithin, tetraglycol and dimethyl isosorbide to about70-75° C. Dissolve the psilocybin, cholesterol and butylatedhydroxytoluene in the heated mixture. Stir until complete dissolution isobtained. Heat about one third of the water to 80-95° C. in a separatevessel and dissolve the preservatives methylparaben and propylparaben inthe heated water while stirring. Allow the solution to cool to about 25°C. and then add the disodium edetate, sodium chloride, sodium hydroxideand citric acid. Add the remainder of the water and stir to obtain acomplete solution. Transfer the organic mixture into the aqueous mixtureby means of a vacuum, while homogenizing the combination with ahigh-shear mixer until a homogeneous product is obtained. Add thehydroxypropyl methylcellulose into the biphasic mixture by means of avacuum while homogenizing with a mixer. The homogenizer is a Silversonhigh-shear mixer operating at approximately 3000 rpm. Single bilayeredliposomes are formed. The white lipogel cream is ready for use.

Example 6. Preparation of a Psilocybin Nanoparticle Formulation

Seven hundred and fifty (750) mg (15 mg/ml theoretical) of a diblockcopolymer consisting of the combination of a poly(d,l-lactic acid) ofmass 30 kD and of a PEG of mass 2 kD (PLA-PEG) and 250 mg (5 mg/mltheoretical) of psilocybin is mixed in 20 ml of ethyl acetate (solutionA). 175 mg of lecithin E80 and 90 mg of sodium oleate is dispersed in 50ml of 5% w/v glucose solution (solution B). Solution A is emulsified insolution B with an Ultra-turrax stirrer and the pre-emulsion is thenintroduced into a Microfluidizer 110 S® type homogenizer for 10 minutesat 10° C. The volume of emulsion recovered is about 70 ml (70 g). Theethyl acetate is removed using a rotary evaporator at reduced pressure(100 mm of mercury) to a suspension volume of about 45 ml (45 g).

Example 7. Preparation of a Gel Psilocybin Formulation

Ingredient Quantity (mg/g of formulation) psilocybin 5.0 chitosan 30.0glycerophosphate 80.0 disodium water 880

A 5 ml solution of acetic acid is titrated to a pH of about 4.0, Thechitosan is added to achieve a pH of about 5.5. The psilocybin is thendissolved in the chitosan solution. This solution is sterilized byfiltration. A 5 ml aqueous solution of glycerophosphate di sodium isalso prepared and sterilized. The two solutions are mixed and within 2 hat 37° C., the desired gel is formed.

Example 8. Preparation of a Gel/Liposome Psilocybin Formulation

Ingredient Quantity psilocybin 5.0 mg/g liposomes 15 umol/mlchitosan-glycerophosphate 100.0 mg/g

The liposomes are prepared in the presence of the psilocybin by thereversed-phase evaporation method, where lipids in chloroform orchloroform-methanol (2:1, v/v) are deposited on the sides of a tube byevaporation of the organic solvent. The lipid film is redissolved indiethyl ether and the aqueous phase (pH 7.4 300 mOsm/kg) containing 20mM Hepes and 144 mM NaCl is added. The mixture is sonicated to obtain ahomogeneous emulsion, and then the organic solvent is removed undervacuum. The preparation is extruded to obtain the required liposome sizeand free components removed by size-exclusion chromatography using aSephadex G-50 column (Amersham Pharmacia Biotech, Uppsala, Sweden).

To prepare the chitosan-glycerophosphate formulation, a 5 ml solution ofacetic acid is titrated to a pH of about 4.0. The chitosan is added toachieve a pH of about 5.5. This solution is sterilized by filtration. A5 ml aqueous solution of glycerophosphate di sodium is also prepared andsterilized. The two solutions are mixed and within 2 h at 37° C., andthe desired gel is formed. The chitosan-glycerophosphate solution isgently mixed with the liposomes at room temperature.

Example 9: Clinical Trial to Establish Maximum Dose of Psilocybinwithout Incidence of a Hallucinogenic Event

Adult individuals (e.g. aged 25-50 in humans) are administered varyingdoses of a 5HT receptor agonist (e.g. psilocybin) with the primaryendpoint to establish at what dose individuals experience ahallucinogenic event. The trial also involves administering the 5HTreceptor agonist at various frequencies (e.g. daily, every other day,twice a week, once a week, once every two weeks and the like) with theendpoint to determine the most effective dosing regimen, withoutexperiencing a hallucinogenic event. This dose, or lower, and dosingregimen is used in the clinical trials described below. Separate cohortsof individuals are administered different dosage forms, with a firstcohort being administered an immediate release 5HT receptor agonist, asecond cohort being administered a controlled release 5HT receptoragonist, a third cohort being administered a dosage form (orcombination) comprising an immediate release component (e.g. coating)and a controlled release component (core), each component comprising 5HTreceptor agonist, and a fourth cohort administered the similar dosageform as the third cohort, with the exception that the controlled releasecomponent further comprises an additional agent (e.g. anti-inflammatoryagent).

Example 10. Effects of 5HT Receptor Agonist in Major Depressive Disorder

The depression lowering activity of 5HT receptor agonist (e.g.psilocybin), administered under four dosing regimens (once daily, everyother day, once weekly, and twice weekly) is investigated in adouble-blind, placebo-controlled, parallel-group, randomized, 12 weekstudy in depressed adult volunteers.

In human individuals, the study is performed in compliance with thecurrent version of the declaration of Helsinki and with the ICH note forguidance on good clinical practice.

For human individuals, depressed individuals, aged 18-55 yearsinclusive, with a body mass index (BMI) within 18-30 kg/m² inclusive,having provided a written informed consent, non-smokers for at least 6months, not using any drug treatment for 2 weeks before screening (2months for enzyme-inducing drugs) except occasional acetaminophen. Theindividuals are confined at a clinical site beginning the day beforedose administration until 72 hours after final dose administration onDay 17 and return for a follow-up visit on Day 21±1.

Endpoints

The primary efficacy endpoint is:

a. Individual assessment of depression using the Montgomery AsbergDepression Rating Scale

The secondary efficacy endpoints are:

a. Individual assessment of change in mood symptoms using theGRID-Hamiltonb. Recorded hallucinogenic experiences

Treatment Regimen

Individuals are randomized into sixteen groups:

Group 1 (n=5): Placebo administered once weeklyGroup 2 (n=10): Immediate release 5HT receptor agonist administered onceweeklyGroup 3 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered every other dayGroup 10 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 11 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 13 (n=5): Placebo administered dailyGroup 14 (n=10): Immediate release 5HT receptor agonist administereddailyGroup 15 (n=10): Controlled release 5HT receptor agonist administereddailyGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered daily

The study is performed using drug supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 11. Effects of 5HT Receptor Agonist in Obsessive-CompulsiveDisorder (OCD)

The activity of 5HT receptor agonist (e.g. psilocybin) to reduce thesymptoms of OCD, administered under four dosing regimens (once daily,every other day, once weekly, and twice weekly) is investigated in adouble-blind, placebo-controlled, parallel-group, randomized, 2 weekstudy in adult volunteers with a diagnosis of OCD.

In human individuals, the study is performed in compliance with thecurrent version of the declaration of Helsinki and with the ICH note forguidance on good clinical practice.

For human individuals, with a formal clinical diagnosis of depression,aged 20-60 years inclusive, with a body mass index (BMI) within 18-30kg/m² inclusive, having provided a written informed consent, not usingany drug treatment for 2 weeks before screening (2 months forenzyme-inducing drugs) except occasional Acetaminophen. The individualsare confined at a clinical site beginning the day before doseadministration until 72 hours after final dose administration on Day 17and return for a follow-up visit on Day 21±1.

Endpoints

The primary efficacy endpoints are:a. Individual assessment of changes in OCD symptoms as measured on AcuteYale-Brown Obsessive-Compulsive Scale (A-YBOCS)b. Effects on Obsessive-Compulsive symptom severityThe secondary efficacy endpoints are:a. Individual assessment of change in mood symptoms using theGRID-Hamiltonb. Recorded hallucinogenic experiences

Treatment Regimen

Individuals are randomized into sixteen groups:Group 1 (n=5): Placebo administered once weeklyGroup 2 (n=10): Immediate release 5HT receptor agonist administered onceweeklyGroup 3 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered every other dayGroup 10 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 11 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 13 (n=5): Placebo administered dailyGroup 14 (n=10): Immediate release 5HT receptor agonist administereddailyGroup 15 (n=10): Controlled release 5HT receptor agonist administereddailyGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered dailyThe study is performed using drug, supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 12. 5HT Receptor Agonist Facilitated Smoking Cessation

The ability of 5HT receptor agonist (e.g. psilocybin) to aid in smokingcessation (or to reduce nicotine dependence, or as Nicotine ReplacementTherapy), administered under four dosing regimens (once daily, everyother day, once weekly, and twice weekly) is investigated in adouble-blind, placebo-controlled, parallel-group, randomized, 8 weekstudy in human adults smoking an average of at least ten cigarettesdaily.

The study is performed in compliance with the current version of thedeclaration of Helsinki and with the ICH note for guidance on goodclinical practice.

Male and female individuals smoking an average of at least tencigarettes daily, aged 20-60 years inclusive, with a body mass index(BMI) within 18-30 kg/m² inclusive, having provided a written informedconsent, not using any drug treatment for 2 weeks before screening (2months for enzyme-inducing drugs) except occasional Acetaminophen.

Endpoints

The primary efficacy endpoints are:a. Days to first cigaretteb. Number of cigarette free daysc. Number of cigarettes per dayThe secondary efficacy endpoints are:a. Number and severity of nicotine cravingsb. Recorded hallucinogenic experiencesIndividuals are randomized into sixteen groups:Group 1 (n=5): Placebo administered once weeklyGroup 2 (n=10): Immediate release 5HT receptor agonist administered onceweeklyGroup 3 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered every other dayGroup 10 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 11 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 13 (n=5): Placebo administered dailyGroup 14 (n=10): Immediate release 5HT receptor agonist administereddailyGroup 15 (n=10): Controlled release 5HT receptor agonist administereddailyGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered dailyThe study is performed using drug supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 13. 5HT Receptor Agonist Facilitated Reduction in AlcoholDependence

The ability of 5HT receptor agonist (e.g. psilocybin) to reduce alcoholdependence when administered under four dosing regimens (every otherday, once weekly, twice weekly, and once every three weeks) isinvestigated in a double-blind, placebo-controlled, randomized, 3 monthstudy in adult males consuming at least 5 units of alcohol daily, everyday.

The study is performed in compliance with the current version of thedeclaration of Helsinki and with the ICH note for guidance on goodclinical practice.

Adult males consuming at least 5 units of alcohol daily, every day,(where one unit of alcohol is: one single measure of spirits (ABV37.5%); half a pint of average-strength (4%) beer or lager; one glass(85 mL) of average-strength (12%) wine), aged 25-65 years inclusive,having provided a written informed consent, not using any drug treatmentfor 2 weeks before screening (2 months for enzyme-inducing drugs) exceptoccasional Acetaminophen.

Endpoints

The primary efficacy endpoints are:a. Number of alcohol free daysb. Number of alcoholic drinks consumed per dayc. Number of heavy drinking days (defined as >4 units per day)The secondary efficacy endpoints are:a. Number and severity of alcohol cravingsb. Individual assessment of change in mood symptoms using theGRID-Hamiltonc. Recorded hallucinogenic experiences

Treatment Regimen

Individuals are randomized into sixteen groups:Group 1 (n=5): Placebo administered every other dayGroup 2 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 3 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered once weeklyGroup 10 (n=10): Immediate release 5HT receptor agonist administeredonce weeklyGroup 11 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 13 (n=5): Placebo administered once every three weeksGroup 14 (n=10): Immediate release 5HT receptor agonist administeredGroup 15 (n=10): Controlled release 5HT receptor agonist administeredGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered daily

The study is performed using drug supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 14. 5HT Receptor Agonist for the Treatment of Migraine Headache

The ability of 5HT receptor agonist (e.g. psilocybin) to treat migraineheadache, administered under four dosing regimens (once daily, everyother day, once weekly, and twice weekly) is investigated in adouble-blind, placebo-controlled, randomized, 4 month study in adultsexperiencing an average of at least one migraine headache monthly.

In human individuals, the study is performed in compliance with thecurrent version of the declaration of Helsinki and with the ICH note forguidance on good clinical practice.

Human adults, aged 20-50 years inclusive, experiencing an average of atleast one migraine headache monthly, with a body mass index (BMI) within18-30 kg/m² inclusive, having provided a written informed consent, notusing any drug treatment for 2 weeks before screening (2 months forenzyme-inducing drugs).

Endpoints

The primary efficacy endpoints are:a. Acute change in pain intensity of migraine attacksb. Acute change in nausea/vomitingc. Acute change in photophobiad. Acute change in phonophobiae. Time to first migraine attackf. Change in migraine attack durationg. Change in migraine attack frequency

Treatment Regimen

Individuals are randomized into sixteen groups:Group 1 (n=5): Placebo administered once weeklyGroup 2 (n=10): Immediate release 5HT receptor agonist administered onceweeklyGroup 3 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered every other dayGroup 10 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 11 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 13 (n=5): Placebo administered dailyGroup 14 (n=10): Immediate release 5HT receptor agonist administereddailyGroup 15 (n=10): Controlled release 5HT receptor agonist administereddailyGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered dailyThe study is performed using drug supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 15. Effects of 5HT Receptor Agonist Facilitated Treatment forOpioid Use

The effectiveness of 5HT receptor agonist (e.g. psilocybin) in treatingopioid dependent individuals, administered under four dosing regimens(once daily, every other day, once weekly, and twice weekly) isinvestigated in a double-blind, placebo-controlled, parallel-group,randomized, 16 week study in opioid dependent adults.

In human individuals, the study is performed in compliance with thecurrent version of the declaration of Helsinki and with the ICH note forguidance on good clinical practice.

Male and female individuals actively using one or more opioids (e.g.prescription opioids, such as oxycodone, hydrocodone, fentanyl,tramadol, or illegal opioids, such as heroin), aged 18-55 yearsinclusive, with a body mass index (BMI) within 18-30 kg/m² inclusive,having provided a written informed consent, nonsmokers for at least 6months.

Endpoints

The primary efficacy endpoints are:a. Incidence of opioid use (assessed by urine analysis)b. Longest duration of abstinencec. Number of abstinence daysd. Number of participants retained in studye. Number of abstinent participantsThe secondary efficacy endpoints are:a. Number and severity of drug cravingsb. Recorded hallucinogenic experiencesIndividuals are randomized into sixteen groups:Group 1 (n=5): Placebo administered once weeklyGroup 2 (n=10): Immediate release 5HT receptor agonist administered onceweeklyGroup 3 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered every other dayGroup 10 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 11 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 13 (n=5): Placebo administered dailyGroup 14 (n=10): Immediate release 5HT receptor agonist administereddailyGroup 15 (n=10): Controlled release 5HT receptor agonist administereddailyGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered dailyThe study is performed using drug supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 16: 5HT Receptor Agonist in the Treatment of Cocaine UseDisorder (CUD)

The effectiveness of 5HT receptor agonist (e.g. psilocybin) to reducecocaine use in patients diagnosed with CUD administered under fourdosing regimens (once daily, every other day, once weekly, and twiceweekly) is investigated in a double-blind, placebo-controlled,parallel-group, randomized, 16 week study in adults diagnosed with CUD.

In human individuals, the study is performed in compliance with thecurrent version of the declaration of Helsinki and with the ICH note forguidance on good clinical practice.

For human individuals, with a clinical diagnosis of CUD, aged 18-65years inclusive, with a body mass index (BMI) within 18-30 kg/m²inclusive, having provided a written informed consent, non-smokers forat least 6 months, not using any drug treatment for 2 weeks beforescreening (2 months for enzyme-inducing drugs) except occasionalacetaminophen and cocaine.

Endpoints

The primary efficacy endpoint is:a. The difference between treatment and placebo groups in the number ofparticipants demonstrating cocaine abstinenceThe secondary efficacy endpoints are:b. Recorded hallucinogenic experiences

Treatment Regimen

Individuals are randomized into sixteen groups:Group 1 (n=5): Placebo administered once weeklyGroup 2 (n=10): Immediate release 5HT receptor agonist administered onceweeklyGroup 3 (n=10): Controlled release 5HT receptor agonist administeredonce weeklyGroup 4 (n=10): Immediate release+controlled release 5HT receptoragonist administered once weeklyGroup 5 (n=5): Placebo administered twice weeklyGroup 6 (n=10): Immediate release 5HT receptor agonist administeredtwice weeklyGroup 7 (n=10): Controlled release 5HT receptor agonist administeredtwice weeklyGroup 8 (n=10): Immediate release+controlled release 5HT receptoragonist administered twice weeklyGroup 9 (n=5): Placebo administered every other dayGroup 10 (n=10): Immediate release 5HT receptor agonist administeredevery other dayGroup 11 (n=10): Controlled release 5HT receptor agonist administeredevery other dayGroup 12 (n=10): Immediate release+controlled release 5HT receptoragonist administered every other dayGroup 13 (n=5): Placebo administered dailyGroup 14 (n=10): Immediate release 5HT receptor agonist administereddailyGroup 15 (n=10): Controlled release 5HT receptor agonist administereddailyGroup 16 (n=10): Immediate release+controlled release 5HT receptoragonist administered dailyThe study is performed using drug supplied as tablets, administeredorally with water, e.g. 30 minutes after a standard meal. Matchingplacebo tablets are supplied.

Example 17: Psilocybin Dose and Efficacy Studies Dose FindingExperiments

Psilocybin was tested at a dose range of 0.03-10.0 mg/kg administeredsubcutaneously (S.C.) Behavioral syndrome including wet dog shakes (WDS)and back muscle contractions (BMC) are characteristic of 5-HT_(2A)receptor activity and potentially indicative of psychomotor signs.Psilocybin dosed 0.03-0.1 mg/kg S.C. produced no signs of behavioralsyndrome, whereas doses of 0.3 mg/kg I.P and higher produced significantsigns of behavior syndrome. These results suggest that a dose range of0.03-0.1 mg/kg S.C. is preferred for examining precognitive ormotivational-enhancing effects of psilocybin (FIG. 1). There is aparallel between behaviors such as WDS in rats and hallucination inhumans (Behavioral Neurobiology of Psychedelic Drugs, Halberstadt, Adam,Vollenweider, Franz X., Nichols, David E. (Eds.), Springer, 2018, p161).

Compared with stimulant drugs, low doses of psilocybin produce a mildstimulant effect, with distance travelled at low doses producingincreases of ˜0.3-0.4 fold in distance travelled (FIG. 2A) and highdoses showing slightly decreased distanced travelled. Stimulant drugscause far larger increases in distance travelled with escalating doses,reflective of a direct motor stimulant property not seen withpsilocybin.

Efficacy Studies

Experiments were conducted to test psilocybin doses in the range of0.05-0.2 mg/kg psilocybin administered S.C. across progressive ratio(PR) and 5-choice serial reaction time task (5CSRTT) to examine theeffect of psilocybin on endophenotypes of motivation and attention. Ineach study, a population of out-bred Long Evans rats was first tested asa group for response to the PR and 5CSRTT. Each group was then dividedinto sub-groups by tertiles according to performance, and then exposedto various dose levels immediately prior to re-testing at variouspsilocybin dose levels. As explained below, rats in the lowest tertilesub-group displayed different responses than rats in the highesttertile.

The PR test is used to answer how willing the test subject is to workfor food (i.e. test of motivation). A single 45 mg food pellet (i.e.reinforcer) is made available to the test animal based on lever pressresponse. To obtain each successive pellet, the animal must makeincreasingly more lever presses. Typically, a progression of 2, 4, 6, 9,12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, etc. is used, derived fromthe equation:

ratio = [5 × e^((0.2 × reinforcer  £)) − 5]

Hungry test animals do not find 45 mg food pellets sufficient and,therefore, there is a drive to repeatedly lever press to obtain multiplefood pellets. At some point, the animal gives up as the motor demands toobtain a single pellet are not deemed worthwhile (i.e. animal reaches“break point” defined as animal's failure to earn a food pellet in 20minutes).

Psilocybin was administered to rats S.C. at doses of 0.05, 0.1 and 0.2mg/kg. None of these doses were observed to cause obvious changes in thenumber of lever presses or break points (i.e. rewards earned) whenstudied across entire study population of 36 rats.

Rats were then sub-grouped into tertiles based on the number of leverpresses for food at baseline, so that within the test population of 36animals, 12 animals were identified as low responders, characterized bylow motivation and potentially corresponding to low motivationendophenotype representative of clinical depression. Twelve animals wereidentified as high responders. There was a statistically significantdifference between the high and low responders. Psilocybin doses of0.05-0.2 mg/kg administered S.C. were observed to produce no effect onresponse in high responder subgroup (FIG. 2). However, 0.05 mg/kgpsilocybin was observed to produce an increase in food responding in lowresponder subgroup, whereas the dose of 0.1 mg/kg did not produce anincrease in food responding. This represents a motivational enhancingeffect of psilocybin in the cohort corresponding to a low motivationendophenotype representative of clinical depression.

The 5CSRTT involves evaluating test subject response to a brief visualstimulus (Higgins, Guy & Silenieks, Leonardo. (2017). Rodent Test ofAttention and Impulsivity: The 5-Choice Serial Reaction Time Task: The5-Choice Serial Reaction Time Task. 10.1002/cpph.27). Animals aretrained to make a nose-poke response to a stimulus location in order tocollect a food reward. The task allows the experimenter to measureanimal performance in multiple domains including:

-   -   Attention    -   Impulsivity    -   Perseveration    -   Speed of response

A strength of the test is its flexible configuration to challenge testsubjects:

-   -   Standard test conditions (0.75 s stimulus duration (SD), 5 s        inter-trial interval (ITI), 100 trials)    -   Multiple short stimulus duration (mSD) (0.03-1 s SD)    -   Fixed long ITI (5 s vs. 10 s ITI)    -   Multiple ultrashort ITI (2-5 s ITI)    -   Extended 250 trials

Psilocybin dose of 0.05 mg/kg administered S.C. was observed to producean increased (p=0.05, t-test) pro-cognitive effect (measured as % hit,calculated as #correct/(#correct+#incorrect+#omissions)*100) whenstudied across a study population of 24 rats in a 5CSRTT with standardconditions, i.e. 0.75s SD, 5S ITI, 100 trials. Asterisk (*) indicatesstatistical significance vs. vehicle. (FIG. 3A). There was a slightnon-significant increase in precognitive effect (measured as % correct,calculated as #correct/(#correct+#incorrect)*100 (FIG. 3B). There was noeffect on performance, e.g no effect on response speed, or number oftrials completed. There was no effect on premature or perseverativeresponses in this experiment.

When this population is segmented into tertiles according to performancebased on accuracy (% correct, calculated as#correct/(#correct+#incorrect)*100), the lowest performing tertile (N=8)are considered to be low attentive and potentially representative of alow attentive endophenotype of depression (FIG. 6A). Low attentive ratsalso score poorly on % hit (FIG. 6B) and have a slower response speed(FIG. 6D). Similar to the PR test, the effect of 0.05 and 0.1 mg/kgpsilocybin on accuracy (% correct and % hit) in the 5CSRTT was observedto be strongly evident in the low attentive subgroup compared withvehicle (FIGS. 6C and 6E). Asterisk (*) indicates statisticalsignificance vs. vehicle. Psilocybin 0.05 mg/kg also increased responsespeed in the low attentive cohort compared with vehicle (FIG. 6D).

Using a longer duration between stimulus and reward, the 5CSRTT studymeasures premature (PREM) and perseverant (PSV) responses. PREM/PSVresponses were increased by increasing the ITI from 5 s (baseline) to 10s (test condition). A psilocybin dose of 0.05 mg/kg administered S.C.was observed to produce an increase (p=0.05, t-test) increase in PREMand PSV responses under a 10 s ITI when studied across a studypopulation of 24 rats (FIG. 4A). Low responders (N=8) were observed toimprove significantly from psilocybin administration at both 0.05 and0.1 mg/kg doses (FIG. 4B, p<0.01, t-test), with marked increases inpremature responses and perseverative responses in rats in thatsub-group compared with vehicle. Both PREM and PSV behaviors areexamples of executive cognitive function, likely involving areas of theprefrontal cortex, a brain region rich in 5-HT_(2A) receptors.

At doses that did not produce effects in animals indicative ofhallucination, improved results were seen on low performing animals onmeasures of motivation, attention, accuracy, speed of response,perseveration, and cognitive engagement. The improvement in the lowperforming animals indicates utility of non-hallucinogenic doses ofpsilocybin in treatment of behavioral and cognitive disorders involvingthese behaviors, including but not limited to depression, anxiety,apathy and low motivation, attention disorders, disorders of executivefunction and cognitive engagement, obsessive compulsive disorder, andneurocognitive disorders. At these same doses, no detrimental effects ofpsilocybin were noted on performance, i.e. there was no evidence ofreduced motivation, impaired motor control, or impaired attention orresponse speed. The positive effects of the low doses of psilocybinappear most evident in the low performer subgroups based on three tests:one PR (motivation) and two 5CSRTT (attention) studies were conducted,using psilocybin at 0.05-0.2 mg/kg (PR) and 0.05-0.1 mg/kg S.C.(5CSRTT). Significant improvements were noted in the low performinganimals on:

-   -   Number of lever presses and increased break point in PR test        (0.05 mg/kg)    -   % Correct and % Hit in 5CSRTT (0.05 and 0.1 mg/kg)    -   Increased speed of responding in 5CSRTT (0.05 mg/kg)    -   PREM/PSV in 5CSRTT 10 s ITI (0.05 and 0.1 mg/kg

Example 18: Psilocybin and Psilocin Pharmacokinetics (PK)

Psilocybin doses of 0.05, 0.1, 1, 10 mg/kg were used to evaluatepsilocybin and psilocin PK in rats. For the doses of psilocybin thatpositively effect behaviors in the low performers in the PR and 5CSRTT,i.e. 0.05-0.1 mg/kg, the corresponding C_(max) of psilocin was ˜7±2ng/ml at 30 minutes for 0.05 mg/kg, and at a dose of 0.1 mg/kg, theC_(max) of psilocin was determined to be ˜12±3 ng/ml at 30 minutes (FIG.5).

Details of the plasma concentration studies are shown in Tables 1-8(psilocybin) and 9-16 (psilocin). Values in italics are below the lowerlevel of quantitation (BLQ, <1 ng/mL) but were included in calculations.Values in bold and underlined are considered to be outliers and wereomitted from calculations. Measured dosing solution concentrations were0.0460, 0.0967, 0.948 and 9.65 mg/mL for 0.05, 0.1, 1 and 10 mg/mLrespectively.

TABLE 1 Plasma concentrations of psilocybin following 0.05 mg/kg s.c.administration. Plasma concentration Experimental (ng/mL) time (h) MeanSD 0.25 6.20 7.27 0.5 12.5 16.9 0.75 1.07 0.348 1 19.2 26.3 2 0.594 n/a4 1.95 0.508 6 2.12 n/a n/a = not applicable

TABLE 2 Plasma concentration of psilocybin following 0.1 mg/kg s.c.administration. Plasma concentration Experimental (ng/mL) time (h) MeanSD 0.25 21.7 27.4 0.5 28.9 45.0 0.75 2.96 1.32 1 2.19 0.605 2 1.76 n/a 42.55 n/a 6 0.921 n/a

TABLE 3 Plasma concentration of psilocybin following 1.0 mg/kg s.c.administration Plasma concentration Experimental (ng/mL) time (h) MeanSD 0.25 75.2 39.8 0.5 47.3 24.4 0.75 35.8 13.2 1 35.1 30.4 2 2.19 1.26 41.12 n/a 6 0.929 n/a

TABLE 4 Plasma concentration of psilocybin following 10 mg/kg s.c.administration. Plasma concentration Experimental (ng/mL) time (h) MeanSD 0.25 1030 832 0.5 1544 1898 0.75 344 132 1 269 93.4 2 101 172 4 1.800.985 6 1.32 1.02

TABLE 5 Plasma PK parameters summary for psilocybin following 0.05 mg/kgs.c. administration. Parameter Mean SD t_(max) (h) 0.600 0.379 C_(max)(ng/mL) 18.9 20.9 C_(max)/Dose (kg * ng/mL/mg) 377 419 Apparent t_(1/2)(h) n/a^(b) n/a AUC_(0-tlast) (h * ng/mL) 10.7 7.08 AUC_(0-inf) (h *ng/mL) n/a n/a AUC_(0-inf)/Dose (h * kg * ng/mL/mg) n/a n/a MRT_(0-inf)(h) n/a n/a n/a = not applicable T_(max) = time at which maximumconcentration is observed C_(max) = maximum observed concentrationApparent t_(1/2) = apparent terminal half-life AUC_(0-tlast) = AreaUnder the Concentration vs time curve from time 0 to the time of thelast measurable concentration AUC_(0-inf) = Area Under the Concentrationvs time curve from time to infinity MRT_(0-inf) = Mean Residence Timefrom time zero to infinity

TABLE 6 Plasma PK parameters summary for psilocybin following 0.1 mg/kgs.c. administration. Parameter Mean SD t_(max) (h) 0.321 0.122 C_(max)(ng/mL) 31.4 39.9 C_(max)/Dose (kg * ng/mL/mg) 314 399 Apparent t_(1/2)(h) n/a^(b) n/a AUC_(0-tlast) (h * ng/mL) 11.4 11.9 AUC_(0-inf) (h *ng/mL) n/a n/a AUC_(0-inf)/Dose (h * kg * ng/mL/mg) n/a n/a MRT_(0-inf)(h) n/a n/a

TABLE 7 Plasma PK parameters summary for psilocybin following 1.0 mg/kgs.c. administration. Parameter Mean SD t_(max) (h) 0.357 0.283 C_(max)(ng/mL) 78.3 39.8 C_(max)/Dose (kg*ng/mL/mg) 78.3 39.8 Apparent t_(1/2)(h) 0.445 0.236 AUC_(0−tlast) (h*ng/mL) 53.1 23.7 AUC_(0−inf) (h*ng/mL)47.9 17.6 AUC_(0−inf) /Dose (h*kg*ng/mL/mg) 47.9 17.6 MRT_(0−inf) (h)0.746 0.186

TABLE 8 Plasma PK parameters summary for psilocybin following 10 mg/kgs.c. administration. Parameter Mean SD t_(max) (h) 0.500 0.289 C_(max)(ng/mL) 3595 4663 C_(max)/Dose (kg*ng/mL/mg) 359 466 Apparent t_(1/2)(h) 0.566 0.189 AUC_(0−tlast) (h*ng/mL) 1707 2338 AUC_(0−inf) (h*ng/mL)2156 2704 AUC_(0−inf) /Dose (h*kg*ng/mL/mg) 216 270 MRT_(0−inf) (h)0.716 0.175

TABLE 9 Plasma concentrations of psilocin following 0.05 mg/kg s.c.administration of psilocybin. Plasma concentration Experimental (ng/mL)time (h) Mean SD 0.25 3.76 0.560 0.5 5.68 3.38 0.75 3.11 0.245 1 5.914.31 2 2.23 1.18 4 0.490 0.253 6 0.136 0.0749

TABLE 10 Plasma concentrations of psilocin following 0.1 mg/kg s.c.administration of psilocybin. Plasma concentration Experimental (ng/mL)time (h) Mean SD 0.25 9.35 2.79 0.5 12.3 8.29 0.75 7.73 1.87 1 5.70 1.522 2.78 n/a 4 0.535 n/a 6 0.215 n/a

TABLE 11 Plasma concentrations of psilocin following 1 mg/kg s.c.administration of psilocybin. Plasma concentration Experimental (ng/mL)time (h) Mean SD 0.25 74.5 16.7 0.5 76.6 11.1 0.75 70.3 7.05 1 69.9 15.52 29.7 4.76 4 5.50 2.21 6 1.34 0.551

TABLE 12 Plasma concentrations of psilocin following 10 mg/kg s.c.administration of psilocybin. Plasma concentration Experimental (ng/mL)time (h) Mean SD 0.25 704 327 0.5 898 266 0.75 1081 437 1 1067 367 2 713255 4 269 126 6 132 53.3

TABLE 13 Plasma PK parameters summary for psilocin following 0.05 mg/kgs.c. administration of psilocybin. Parameter Mean SD t_(max) (h) 0.6000.379 C_(max) (ng/mL) 7.14 4.02 Apparent t_(1/2) (h) 1.00 0.227AUC_(0−tlast) (h*ng/mL) 10.1 3.96 AUC_(0−inf) (h*ng/mL) 10.3 3.92MRT_(0−inf) (h) 1.73 0.177

TABLE 14 Plasma PK parameters summary for psilocin following 0.1 mg/kgs.c. administration of psilocybin. Parameter Mean SD t_(max) (h) 0.5360.267 C_(max) (ng/mL) 11.7 6.81 Apparent t_(1/2) (h) 0.918 0.22AUC_(0−tlast) (h*ng/mL) 12.5 6.42 AUC_(0−inf) (h*ng/mL) 15.7 5.56MRT_(0−inf) (h) 1.42 0.337

TABLE 15 Plasma PK parameters summary for psilocin following 1 mg/kgs.c. administration of psilocybin. Parameter Mean SD t_(max) (h) 0.5710.313 C_(max) (ng/mL) 83.3 14.4 Apparent t_(1/2) (h) 0.878 0.0762AUC_(0−tlast) (h*ng/mL) 117 45.2 AUC_(0−inf) (h*ng/mL) 143 20.4MRT_(0−inf) (h) 1.53 0.110

TABLE 16 Plasma PK parameters summary for psilocin following 10 mg/kgs.c. administration of psilocybin. Parameter Mean SD t_(max) (h) 0.7140.267 C_(max) (ng/mL) 1106 434 Apparent t_(1/2) (h) 1.65 0.325AUC_(0−tlast) (h*ng/mL) 2280 1524 AUC_(0−inf) (h*ng/mL) 3376 1056MRT_(0−inf) (h) 2.66 0.395

While preferred embodiments have been shown and described herein, itwill be obvious to those skilled in the art that such embodiments areprovided by way of example only. Numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from this disclosure. It should be understood that variousalternatives to the embodiments described herein might be employed inpracticing current disclosure.

NUMBERED EMBODIMENTS

Embodiment 1 is a pharmaceutical composition comprising:

a) a therapeutically effective amount of one or more 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof,

b) a pharmaceutically acceptable excipient, and

c) optionally one or more agents selected from the group consisting ofsurfactants, preservatives, flavoring agents, sweetening agents, andantifoaming agents.

Embodiment 2 is the pharmaceutical composition of embodiment 1, whereinthe pharmaceutical composition is a low-dose pharmaceutical composition.

Embodiment 3 is the pharmaceutical composition of embodiment 2, whereinthe therapeutically effective amount of 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is present in an amount insufficient to provide anadverse side effect, such as hallucinogenic experience.

Embodiment 4 is the pharmaceutical composition of either one ofembodiments 2 or 3, wherein following administration to an individual inneed thereof, the low-dose pharmaceutical composition provides a maximumplasma concentration (C_(max)) of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof of less than 6 ng/mL in the individual in need thereof.

Embodiment 5 is the pharmaceutical composition of any one of thepreceding embodiments, wherein following administration to an individualin need thereof, the low-dose pharmaceutical composition provides amaximum plasma concentration (C_(max)) of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof of at least 0.5 ng/mL and less than 6 ng/mL in theindividual in need thereof (e.g. about 1 ng/mL to about 5.5 ng/mL, about2 ng/mL to about 5 ng/mL, or the like).

Embodiment 6 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the pharmaceutical composition comprisesa controlled release component.

Embodiment 7 is the pharmaceutical composition of any one of thepreceding embodiments, wherein following administration to an individualin need thereof, the pharmaceutical composition provides a minimumplasma concentration (C_(min)) of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof of about 0.1 ng/mL or more in the individual, whereinthe minimum plasma concentration (C_(min)) is determined at a timebetween 2 hours and 12 hours (or between 2 hours and 24 hours, orbetween 2 hours and 48 hours, or between 2 hours and 72 hours, or thelike) after administration to the individual.

Embodiment 8 is the pharmaceutical composition of any one of thepreceding embodiments, wherein following administration to an individualin need thereof, the pharmaceutical composition provides a minimumplasma concentration (C_(max)) of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof of about 0.1 ng/mL to about 0.5 ng/mL in the individual,wherein the minimum plasma concentration (C_(min)) is determined at atime between 2 hours and 12 hours (or between 2 hours and 24 hours, orbetween 2 hours and 48 hours, or between 2 hours and 72 hours, or thelike) after administration to the individual.

Embodiment 9 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the pharmaceutical composition comprisesa controlled release component and an immediate release component.

Embodiment 10 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the pharmaceutical composition is an oralformulation, a buccal formulation, a nasal formulation, or an inhalationformulation.

Embodiment 11 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the pharmaceutically acceptable excipientcomprises water, purified water, saline, liposome, mineral oil, alcohol,or any combination thereof.

Embodiment 12 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the composition further comprises aneffective amount of a vasoconstrictor.

Embodiment 13 is the pharmaceutical composition of embodiment 12,wherein the vasoconstrictor is epinephrine, phenylephrine, methoxamine,norepinephrine, zolmitriptan, tetrahydrozaline, naphazoline, orcombinations thereof.

Embodiment 14 is the pharmaceutical composition of any one ofembodiments 1-13, wherein the composition further comprises an effectiveamount of a stimulant, an antihistamine, an antiemetic, anantidepressant, an anti-inflammatory, a growth factor, a lithiumcompound, resveratrol, phosphatidylcholine, curcumin, magnesium,melatonin, pregnenolone, ginseng, tryptophan, lysergic aciddiethylamide, a 5HT receptor antagonist, or combinations thereof.

Embodiment 15 is the pharmaceutical composition of any one of thepreceding embodiments, wherein said composition is in a form selectedfrom a spray, aerosol, mist, nebulae, ointment, cream, gel, paste,salve, solution, suspension, tincture, patch, and atomized vapor.

Embodiment 16 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is present in an amount of about 0.1 mg to about 50 mg(e.g. about 0.1 mg to about 10 mg, or about 0.2 mg to about 5 mg.

Embodiment 17 is the pharmaceutical composition of any one of thepreceding embodiments, further comprising a controlled release matrix.

Embodiment 18 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is between about 2 ng/ml and 6ng/ml.

Embodiment 19 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is between about 2 ng/ml andabout 5 ng/ml.

Embodiment 20 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is between about 4 ng/ml and 6ng/ml.

Embodiment 21 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is between about 2 ng/ml andabout 4 ng/ml.

Embodiment 22 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is about 1 ng/ml to about 4ng/ml.

Embodiment 23 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is about 1 ng/ml to about 4ng/ml.

Embodiment 24 is the pharmaceutical composition of embodiment 17,wherein the maximum plasma concentration is about 1 ng/ml or more uponoral administration to a subject in need thereof.

Embodiment 25 is the pharmaceutical composition of any one ofembodiments 17-24, wherein the minimum plasma concentration (C_(min)) isbetween about 0.1 ng/ml and about 0.4 ng/ml.

Embodiment 26 is the pharmaceutical composition of any one ofembodiments 17-24, wherein the minimum plasma concentration (C_(min)) isbetween about 0.2 ng/ml and about 0.4 ng/ml.

Embodiment 27 is the pharmaceutical composition of any one ofembodiments 17-24, wherein the minimum plasma concentration (C_(min)) isat most about 0.4 ng/ml.

Embodiment 28 is the pharmaceutical composition of any one ofembodiments 17-27, wherein said composition comprises no more than 5 mgof the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof

Embodiment 29 is the pharmaceutical composition of any one ofembodiments 17-27, wherein said composition comprises no more than 3 mgof the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof.

Embodiment 30 is the pharmaceutical composition of any one ofembodiments 17-27, wherein said composition comprises about 5 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 31 is the pharmaceutical composition of any one ofembodiments 17-27, wherein said composition comprises about 3 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 32 is the pharmaceutical composition of any one ofembodiments 17-31, wherein said composition is formulated to beadministered to a subject in need thereof about once a week.

Embodiment 33 is the pharmaceutical composition of any one ofembodiments 17-31, wherein said composition is formulated to beadministered to a subject in need thereof about once every two weeks.

Embodiment 34 is the pharmaceutical composition of any one ofembodiments 17-33, wherein the minimum plasma concentration (C_(min)) isdetermined at a time between 24 and 48 hours after administration.

Embodiment 35 is the pharmaceutical composition of any one ofembodiments 17-33, wherein the minimum plasma concentration (C_(min)) isdetermined at a time between 48 and 72 hours after administration.

Embodiment 36 is the pharmaceutical composition of any one ofembodiments 17-33, wherein the minimum plasma concentration (C_(min)) isdetermined at a time between 72 and 96 hours after administration.

Embodiment 37 is the pharmaceutical composition of any one ofembodiments 17-33, wherein the minimum plasma concentration (C_(min)) isdetermined at a time between 96 to 120 hours after administration.

Embodiment 38 is the pharmaceutical composition of any one ofembodiments 17-33, wherein said composition provides the minimum plasmaconcentration (C_(min)) is determined at a time between 120 to 144 hoursafter administration.

Embodiment 39 is the pharmaceutical composition of any one ofembodiments 1-38, wherein the composition comprises an oral dosage form,the oral dosage form comprising a (e.g. immediate-release or controlledrelease) layer or coating and a controlled release core,

the layer or coating comprising (i) one or more 5HT receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof and, optionally, (ii) one or more second agent, the oneor more second agent being a stimulant, an antihistamine, an antiemetic,an antidepressant, an anti-inflammatory, a growth factor, a lithiumcompound, resveratrol, phosphatidylcholine, curcumin, magnesium,melatonin, pregnenolone, ginseng, tryptophan, or lysergic aciddiethylamide, or a 5HT receptor antagonist, or any combination thereof;and the controlled release core comprising:

a) one or more 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof;

b) at least one pharmaceutically acceptable excipient;

c) optionally one or more agents selected from the group consisting ofsurfactants, preservatives, flavoring agents, sweetening agents, andantifoaming agents-; and

d) optionally one or more agents selected from the group consisting ofstimulants, antihistamines, antiemetics, antidepressants,anti-inflammatories, growth factors, lithium compounds, resveratrol,phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone,ginseng, tryptophan, lysergic acid diethylamide, or a 5HT receptorantagonist, and any combination of one or more thereof.

Embodiment 40 is the pharmaceutical composition of any one ofembodiments 1-38, wherein the composition comprises an oral dosage form,the oral dosage form comprising a (e.g. immediate-release or controlledrelease) layer or coating and a controlled release core, the layer orcoating comprising (i) one or more 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof and, optionally, (ii) one or more second agent, the oneor more second agent being a stimulant, an antihistamine, an antiemetic,an antidepressant, an anti-inflammatory, a growth factor, a lithiumcompound, resveratrol, phosphatidylcholine, curcumin, magnesium,melatonin, pregnenolone, ginseng, tryptophan, lysergic aciddiethylamide, or a 5HT receptor antagonist; and the controlled releasecore comprising:

a) one or more 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof (e.g. and oneor more additional active core agent, such as a stimulant, anantihistamine, an antiemetic, an antidepressant, an anti-inflammatory, agrowth factor, a lithium compound, resveratrol, phosphatidylcholine,curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan,lysergic acid diethylamide, a 5HT receptor antagonist, or anycombination thereof);

b) a buffer;

c) water; and

d) optionally one or more agents selected from the group consisting ofpreservatives, flavoring agents, sweetening agents, surfactants,antifoaming agents, and suspension aids.

Embodiment 41 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises at least about 1 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 42 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises at most about 50 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 43 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises from about 1 mg to about50 mg of the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof.

Embodiment 44 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises from about 2 mg to about40 mg of the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof.

Embodiment 45 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises from about 3 mg to about30 mg of the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof.

Embodiment 46 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises from about 5 mg to about20 mg of the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof.

Embodiment 47 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises from about 1 mg to about10 mg of the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof.

Embodiment 48 is the pharmaceutical composition of embodiment 39 or 40,wherein the immediate-release layer comprises about 1 mg, about 2 mg,about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg,about 9 mg, or about 10 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 49 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises atleast about 10 mg of the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof.

Embodiment 50 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises at mostabout 300 mg of the 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof.

Embodiment 51 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 10 mg to about 300 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 52 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 15 mg to about 250 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 53 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 20 mg to about 200 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 54 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 30 mg to about 150 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 55 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 40 mg to about 100 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 56 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 10 mg to about 50 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 57 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises fromabout 10 mg to about 30 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 58 is the pharmaceutical composition of any one ofembodiments 39-48, wherein the controlled release core comprises about10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, or about 50 mg of the 5HT receptor agonist ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 59 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the pharmaceutically acceptable excipientis selected from the group consisting of fillers, binders, suspendingagents, disintegrants, lubricants, and combinations thereof.

Embodiment 60 is the pharmaceutical composition of embodiment 59,wherein said composition comprises a filler.

Embodiment 61 is the pharmaceutical composition of embodiment 60,wherein the amount of the filler is from about 10% to about 20% by totalweight of the composition.

Embodiment 62 is the pharmaceutical composition of embodiment 59,wherein said composition comprises a binder.

Embodiment 63 is the pharmaceutical composition of embodiment 62,wherein the amount of the binder is from about 5% to about 15% by totalweight of the composition.

Embodiment 64 is the pharmaceutical composition of embodiment 59,wherein said composition comprises a suspending agent.

Embodiment 65 is the pharmaceutical composition of embodiment 64,wherein the amount of the suspending agent is from about 1% to about 5%by total weight of the composition.

Embodiment 66 is the pharmaceutical composition of embodiment 59,wherein said composition comprises a disintegrant.

Embodiment 67 is the pharmaceutical composition of embodiment 66,wherein the amount of the disintegrant is from about 1% to about 5% bytotal weight of the composition.

Embodiment 68 is the pharmaceutical composition of embodiment 59,wherein said composition comprises a lubricant.

Embodiment 69 is the pharmaceutical composition of embodiment 68,wherein the amount of the lubricant is from about 1% to about 5% bytotal weight of the composition.

Embodiment 70 is the pharmaceutical composition of any one ofembodiments 39-69, wherein said composition additionally comprises asurfactant.

Embodiment 71 is the pharmaceutical composition of embodiment 70,wherein the amount of the surfactant is from about 0.1% to about 2% bytotal weight of the composition.

Embodiment 72 is the pharmaceutical composition of embodiment 70,wherein the amount of the surfactant is from about 1% to about 15% bytotal weight of the composition.

Embodiment 73 is the pharmaceutical composition of any one ofembodiments 39-72, wherein said composition is a tablet or capsule.

Embodiment 74 is the pharmaceutical composition of embodiment 73,wherein said composition is a capsule.

Embodiment 75 is the pharmaceutical composition of embodiment 73,wherein said composition is a tablet.

Embodiment 76 is the pharmaceutical composition of any one ofembodiments 39-75, wherein said composition additionally comprises apreservative.

Embodiment 77 is the pharmaceutical composition of embodiment 76,wherein the amount of preservative is about 0.1% to about 2% by totalweight of the composition.

Embodiment 78 is the pharmaceutical composition of any one ofembodiments 39-77, wherein said composition additionally comprises anantifoaming agent.

Embodiment 79 is the pharmaceutical composition of embodiment 78,wherein the amount of the antifoaming agent is about 0.1% to about 1% bytotal weight of the composition.

Embodiment 80 is the pharmaceutical composition of any one ofembodiments 39-79, wherein said composition comprises a flavoring agent.

Embodiment 81 is the pharmaceutical composition of any one ofembodiments 39-80, wherein said composition comprises a sweetener.

Embodiment 82 is the pharmaceutical composition of embodiment 39-81,wherein said composition is formulated and/or packaged to be repeatedlyadministered to a subject in need thereof about once a week (or morefrequently, such as two or three times a week, daily, or the like).

Embodiment 83 is the pharmaceutical composition of embodiment 39-81,wherein said composition is formulated and/or packaged to be repeatedlyadministered to a subject in need thereof about once every two weeks (orless frequently).

Embodiment 84 is the pharmaceutical composition of embodiment 39-81,wherein said composition is repeatedly administered to a subject in needthereof about once a month.

Embodiment 85 is the pharmaceutical composition of any one ofembodiments 1-38, wherein the composition comprises a buccal compositioncomprising:

(a) a 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof; and

(b) a matrix which releases the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof at a predetermined rate for transport across buccalmembranes, wherein the matrix comprises one or more compounds selectedfrom:

-   -   (i) taste masking agents,    -   (ii) enhancers,    -   (iii) complexing agents, and mixtures thereof and

(c) one or more of pharmaceutically acceptable excipients.

Embodiment 86 is the pharmaceutical composition of embodiment 85,wherein the composition comprises at least about 10 mg of the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 87 is the pharmaceutical composition of embodiment 85,wherein the composition comprises at most about 300 mg of the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 88 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 10 mg to about 300 mg ofthe 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 89 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 15 mg to about 250 mg ofthe 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 90 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 20 mg to about 200 mg ofthe 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 91 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 30 mg to about 150 mg ofthe 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 92 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 40 mg to about 100 mg ofthe 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof

Embodiment 93 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 10 mg to about 50 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 94 is the pharmaceutical composition of embodiment 85,wherein the composition comprises from about 10 mg to about 30 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 95 is the pharmaceutical composition of embodiment 85,wherein the composition comprises about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, orabout 50 mg of the 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof.

Embodiment 96 is the pharmaceutical composition of any one ofembodiments 85-95, wherein the enhancer is selected from the groupconsisting of surfactants, bile salts, bile salt derivatives, fattyacids, fatty acid derivatives, sulfoxides, chelators, alcohols, polyols,and polymers.

Embodiment 97 is the pharmaceutical composition of any one ofembodiments 1-38, wherein the composition comprises a dosage form fornasal administration comprising:

(a) a therapeutically effective amount of a 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof;

(b) permeation enhancer, and

(c) one or more of pharmaceutically acceptable excipients.

Embodiment 98 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises at most about 5 mg of the 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof.

Embodiment 99 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises at least about 0.5 mg of the 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 100 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises from about 0.5 mg to about 2 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 101 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises from about 0.5 mg to about 5 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof

Embodiment 102 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises from about 1 mg to about 4 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 103 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises from about 2 mg to about 3 mg of the5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof.

Embodiment 104 is the pharmaceutical composition of embodiment 97,wherein the dosage form comprises about 0.5 mg, about 1 mg, about 1.5mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg,about 4.5 mg, or about 5 mg of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 105 is the pharmaceutical composition of any one ofembodiments 97-104, wherein the permeation enhancer is selected from thegroup consisting of bile salts, surfactants, fatty acids, fatty acidderivatives, glycerides, chelators, salicylates, and polymers.

Embodiment 106 is the pharmaceutical composition of any one ofembodiments 97-105, wherein the pharmaceutically acceptable excipient isselected from the group consisting of fillers, binders, suspendingagents, disintegrants, lubricants, and combinations thereof.

Embodiment 107 is the pharmaceutical composition of any one ofembodiments 1-38, wherein the composition comprises a patch comprising(i) a support layer and (ii) an adhesive agent layer, wherein theadhesive agent layer comprises

(a) a 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof, and(b) a rubber-based adhesive agent and/or a silicone-based adhesiveagent.

Embodiment 108 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the 5HT receptor agonist is a 5HT2receptor agonist.

Embodiment 109 is the pharmaceutical composition of embodiment 108,wherein the 5HT2 receptor agonist is one or more of a 5HT_(2A) receptoragonist, a 5HT2B receptor agonist and a 5HT2C receptor agonist.

Embodiment 110 is the pharmaceutical composition of embodiment 108,wherein the 5HT2 receptor agonist is a 5HT_(2A) receptor agonist or a5HT2C receptor agonist.

Embodiment 111 is the pharmaceutical composition of embodiment 108,wherein the 5HT2 receptor agonist is a 5HT_(2A) receptor agonist and a5HT2C receptor agonist.

Embodiment 112 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the 5HT receptor agonist is psilocin or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 113 is the pharmaceutical composition of any one of thepreceding embodiments, wherein the 5HT receptor agonist is psilocybin ora pharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof.

Embodiment 114 is a pharmaceutical composition comprising:

a) a therapeutically effective amount of one or more 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof,

b) a pharmaceutically acceptable excipient, and

c) optionally one or more agents selected from the group consisting ofsurfactants, preservatives, flavoring agents, sweetening agents, andantifoaming agents;

wherein the pharmaceutical composition is a low-dose pharmaceuticalcomposition;wherein following administration to an individual in need thereof, thepharmaceutical composition provides a maximum plasma concentration(C_(max)) of the 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof of less than 6ng/mL in the individual in need thereof; andwherein the 5HT receptor agonist is psilocin or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof orwherein the 5HT receptor agonist is psilocybin or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof.

Embodiment 115 is a pharmaceutical composition comprising an oral dosageform, the oral dosage form comprising an immediate-release top layer anda controlled release core, the immediate-release layer comprising (i)one or more 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof and (ii) one or moresecond agent, the one or more second agent being a stimulant, anantihistamine, an antiemetic, an antidepressant, an anti-inflammatory, agrowth factor, a lithium compound, resveratrol, phosphatidylcholine,curcumin, magnesium, melatonin, pregnenolone, ginseng, or lysergic aciddiethylamide; and the controlled release core comprising:

a) one or more 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof;

b) at least one pharmaceutically acceptable excipient; and

c) optionally one or more agents selected from the group consisting ofsurfactants, preservatives, flavoring agents, sweetening agents, andantifoaming agents;

wherein the pharmaceutical composition is a low-dose pharmaceuticalcomposition; andwherein following administration to an individual in need thereof, thepharmaceutical composition provides a maximum plasma concentration(C_(max)) of the 5HT receptor agonist or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof of less than 6ng/mL in the individual in need thereof.

Embodiment 116 is the pharmaceutical composition of embodiment 115,wherein the 5HT receptor agonist is psilocin or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof.

Embodiment 117 is the pharmaceutical composition of embodiment 115,wherein the 5HT receptor agonist is psilocybin or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof.

What is claimed is:
 1. A method of managing a neurological condition orone or more symptoms thereof in a subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising: a)a therapeutically effective amount of one or more 5HT receptor agonistor a pharmaceutically acceptable salt, solvate, metabolite, derivative,or prodrug thereof; and b) a pharmaceutically acceptable excipientwherein the therapeutically effective amount of the 5HT receptor agonistor a pharmaceutically acceptable salt, solvate, metabolite, derivative,or prodrug thereof is provided to the subject in need thereof in anamount insufficient to provide an adverse side effect, such ashallucinogenic experience.
 2. A method of treating the symptoms of aneurological condition in a subject suffering from or susceptible to theneurological condition, comprising administering to the subject apharmaceutical composition comprising: a) a therapeutically effectiveamount of one or more 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof;and b) a pharmaceutically acceptable excipient; wherein thetherapeutically effective amount of the 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is provided to the subject in need thereof in an amountinsufficient to provide an adverse side effect, such as hallucinogenicexperience.
 3. The method of any one of the preceding claims, whereinthe 5HT receptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is present in an amount offrom about 0.1 mg to about 50 mg (e.g. about 0.1 mg to about 10 mg,about 0.2 mg to about 5 mg, about 10 mg to about 50 mg, or the like). 4.The method of any one of the preceding claims, wherein the 5HT receptoragonist or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof is present in an amount of from about 0.1mg to about 2 mg.
 5. The method of any one of the preceding claims,wherein the 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof is present in anamount of from about 1 mg to about 15 mg.
 6. The method of any one ofthe preceding claims, wherein the pharmaceutical composition is alow-dose pharmaceutical composition.
 7. The method of any one of thepreceding claims, wherein the pharmaceutical composition comprises acontrolled release component.
 8. The method of any one of the precedingclaims, wherein the pharmaceutical composition comprises a controlledrelease component and an immediate release component.
 9. The method ofany one of the preceding claims, wherein the therapeutically effectiveamount of 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof is provided to asubject in need thereof in an amount and/or formulation insufficient toprovide a maximum plasma concentration (C_(max)) of (e.g. active form ofthe) 5HT receptor agonist or a pharmaceutically acceptable salt,solvate, metabolite, derivative, or prodrug thereof of 6 ng/mL or more.10. The method of any one of the preceding claims, wherein thetherapeutically effective amount of 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof is provided to a subject in need thereof in an amountand/or formulation to provide a maximum plasma concentration (C_(max))of (e.g. active form of the) 5HT receptor agonist or a pharmaceuticallyacceptable salt, solvate, metabolite, derivative, or prodrug thereof ofabout 0.1 ng/mL or more and less than 6 ng/mL (e.g. at least 0.5 ng/mLand less than 6 ng/mL, about 1 ng/mL to about 5.5 ng/mL, about 2 ng/mLto about 5 ng/mL, or the like).
 11. The method of any one of thepreceding claims, wherein the therapeutically effective amount of 5HTreceptor agonist or a pharmaceutically acceptable salt, solvate,metabolite, derivative, or prodrug thereof is provided to a subject inneed thereof in an amount and/or formulation to provide a plasmaconcentration of (e.g. active form of the) 5HT receptor agonist or apharmaceutically acceptable salt, solvate, metabolite, derivative, orprodrug thereof of at least 0.1 ng/mL (e.g. at least 0.2 ng/mL, at least0.3 ng/mL, at least 0.5 ng/mL, or the like) after at least 6 hours (e.g.at least 12 hours, at least 24 hours, at least 36 hours, at least 48hours, at least 72 hours, at least 96 hours, at least 120 hours, atleast 144 hours, or the like).
 12. The method of any one of thepreceding claims, wherein the 5HT receptor agonist is a 5HT2 receptoragonist.
 13. The method of any one of the preceding claims, wherein the5HT receptor agonist is psilocybin or a pharmaceutically acceptablesalt, solvate, metabolite, derivative, or prodrug thereof.
 14. Themethod of any one of claims 1-12, wherein the 5HT receptor agonist ispsilocin or a pharmaceutically acceptable salt, solvate, metabolite,derivative, or prodrug thereof.
 15. The method of any one of thepreceding claims, wherein the pharmaceutical composition furthercomprises one or more agents selected from the group consisting ofsurfactants, preservatives, flavoring agents, sweetening agents, andantifoaming agents.
 16. The method of any one of the preceding claims,wherein the pharmaceutical composition is an oral formulation, a buccalformulation, a nasal formulation, or an inhalation formulation.
 17. Themethod of any one of the preceding claims, wherein the pharmaceuticalcomposition is in a form selected from a spray, aerosol, mist, nebulae,ointment, cream, gel, paste, salve, solution, suspension, tincture,patch, and atomized vapor.
 18. The method of any one of the precedingclaims, wherein the pharmaceutical composition further comprises aneffective amount of a second agent.
 19. The method of claim 18, whereinthe second agent is a vasodilator or vasoconstrictor.
 20. The method ofclaim 19, wherein the vasoconstrictor is epinephrine, phenylephrine,methoxamine, norepinephrine, zolmitriptan, tetrahydrozaline,naphazoline, or combinations thereof.
 21. The method of claim 18,wherein the second agent is a stimulant, an antihistamine, anantiemetic, an antidepressant, an anti-inflammatory, a growth factor, alithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium,melatonin, pregnenolone, ginseng, lysergic acid diethylamide, orcombinations thereof.
 22. The method of claim 18, wherein the secondagent is a 5HT receptor antagonist.
 23. The method of claim 18, whereinthe second agent is an anti-psychotic agent.
 24. The method of claim 23,wherein the anti-psychotic agent is olanzapine, clozapine, risperidone,paliperidone, aripiprazole, quetiapine, iloperidone, ziprasidone,asenapine, lurasidone, sertindole, amisulpride, clotiapine, mosapramine,perospirone, sulpiride, zotepine, haloperidol, benperidol, loxapine,molindone, pimozide, thioridazine, mesoridazine, thiothixene,chlorprothixene, fluphenazine, trifluoperazine, chlorpromazine,perphenazine, prochlorperazine, droperidol, and zuclopenthixol.
 25. Themethod of claim 18, wherein the second agent is administeredsimultaneously, sequentially, or alternately with the pharmaceuticalcomposition.
 26. The method of claim 25, wherein the second agent isadministered simultaneously, sequentially, or alternately with thepharmaceutical composition.
 27. The method of claim 25, wherein thepharmaceutical composition is administered first and the second agent isadministered at least once before the pharmaceutical composition isadministered a subsequent time.
 28. The method of claim 25, wherein thepharmaceutical composition is administered first and the second agent isadministered more than once before the pharmaceutical composition isadministered a subsequent time.
 29. The method of any one of thepreceding claims, wherein the pharmaceutical composition is administeredto a subject in need thereof no more frequently than once a day (e.g. nomore frequently than once every other day, no more frequently than onceevery third day, no more frequently than twice a week, no morefrequently than once a week, no more frequently than once every twoweeks, or the like).
 30. The method of any one of the preceding claims,wherein the pharmaceutical composition is administered to a subject inneed thereof once a day, every alternate day, three times a week, twicea week, once a week, every other week, two weeks per month, three weeksper month, once a month, twice a month or three times per month.
 31. Themethod of any one of the preceding claims, wherein the pharmaceuticalcomposition is administered about once a day.
 32. The method of any oneof the preceding claims, wherein the pharmaceutical composition isadministered about every alternate day.
 33. The method of any one of thepreceding claims, wherein the pharmaceutical composition is administeredabout once a week.
 34. The method of any one of the preceding claims,wherein the pharmaceutical composition is administered about once everytwo weeks or more.
 35. The method of any one of the preceding claims,wherein the pharmaceutical composition is administered for at least 1month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years,or 3 years.
 36. The method of any one of the preceding claims, whereinthe neurological condition is a neurological disorder.
 37. The method ofany one of the preceding claims, wherein the neurological condition is aneurocognitive disorder.
 38. The method of any one of the precedingclaims, wherein the symptoms of the neurological condition are physical,behavioral, emotional, mental or a combination thereof.
 39. The methodof any one of the preceding claims, wherein the neurological conditionis an addictive disorder.
 40. The method of claim 39, wherein theaddictive disorder is alcohol abuse, substance abuse, smoking, orobesity.
 41. The method of any one of claims 1-38, wherein theneurological condition is an eating disorder or an auditory disorder.42. The method of any one of claims 1-38, wherein the neurologicalcondition is pain (e.g. chronic pain).
 43. The method of any one ofclaims 1-38, wherein the neurological condition is depression, bipolardisorder, anxiety, social anxiety, post-traumatic stress disorder(PTSD), panic disorder, phobia, schizophrenia, psychopathy, orantisocial personality disorder.
 44. The method of any one of claims1-38, wherein the neurological condition is an impulsive disorder. 45.The method of claim 44, wherein the impulsive disorder is attentiondeficit hyperactivity disorder (ADHD), attention deficit disorder (ADD),Tourette's syndrome or autism.
 46. The method of any one of claims 1-38,wherein the neurological condition is a compulsive disorder.
 47. Themethod of claim 46, wherein the compulsive disorder is obsessivecompulsive disorder (OCD), gambling, or aberrant sexual behavior. 48.The method of any one of claims 1-38, wherein the neurological conditionis a personality disorder.
 49. The method of claim 48, wherein thepersonality disorder is conduct disorder, antisocial personality, oraggressive behavior.